Actinomycetes as Producers of Biologically Active Terpenoids: Current Trends and Patents

Abstract

Terpenes and their derivatives (terpenoids and meroterpenoids, in particular) constitute the largest class of natural compounds, which have valuable biological activities and are promising therapeutic agents. The present review assesses the biosynthetic capabilities of actinomycetes to produce various terpene derivatives; reports the main methodological approaches to searching for new terpenes and their derivatives; identifies the most active terpene producers among actinomycetes; and describes the chemical diversity and biological properties of the obtained compounds. Among terpene derivatives isolated from actinomycetes, compounds with pronounced antifungal, antiviral, antitumor, anti-inflammatory, and other effects were determined. Actinomycete-produced terpenoids and meroterpenoids with high antimicrobial activity are of interest as a source of novel antibiotics effective against drug-resistant pathogenic bacteria. Most of the discovered terpene derivatives are produced by the genus Streptomyces; however, recent publications have reported terpene biosynthesis by members of the genera Actinomadura, Allokutzneria, Amycolatopsis, Kitasatosporia, Micromonospora, Nocardiopsis, Salinispora, Verrucosispora, etc. It should be noted that the use of genetically modified actinomycetes is an effective tool for studying and regulating terpenes, as well as increasing productivity of terpene biosynthesis in comparison with native producers. The review includes research articles on terpene biosynthesis by Actinomycetes between 2000 and 2022, and a patent analysis in this area shows current trends and actual research directions in this field.

1. Introduction

Terpenes and their O-containing derivatives (terpenoids) are the largest (more than 80,000 compounds) and structurally most diverse group of secondary metabolites derived from natural sources. Based on the number of isoprene units, terpene derivatives are classified into mono- (C10), sesqui- (C15), di- (C20), sester- (C25), tri- (C30), sesquar- (C35), and tetra- (C40) terpenes. Terpene derivatives are widely used in the food, cosmetics, and fragrance industries [1]. They exhibit various biological activities (antitumor, anti-inflammatory, antimicrobial, antiviral, immunomodulatory, antioxidant, antifungal, etc.) and are promising therapeutic agents [2]. Production of terpene derivatives from natural sources (plants, fungi, and marine organisms) does not meet industrial needs, while chemical synthesis is often a multi-stage and low selective process.

In the last 15–20 years, it has become obvious that bacteria also produce terpenes and terpenoids and that most of the produced metabolites are represented by new compounds. Currently, the search for microorganisms synthesizing terpene derivatives is underway and microbial biosynthetic platforms are developed using such microorganisms [3]. Microbial biosynthesis has advantages over traditional methods of obtaining terpenoids: a short life cycle of microorganisms, which reduces the production time of compounds to several days, high productivity throughout the fermentation process, and the use of cheap renewable resources to produce target products [4]. The ability for terpene biosynthesis has been described for actino-, proteo-, and cyanobacteria [5,6,7].

Actinomycetes are one of the largest, most diverse and well-studied group of bacteria represented by the genera such as Mycobacterium, Nocardia, Rhodococcus, Streptomyces, Arthrobacter, Actinomyces, Corynebacterium, Micrococcus, Frankia, Micromonospora. They are characterized by a wide range of genetic, morphological, and physiological characteristics, as well as metabolic capabilities [8]. Actinomycetes are well-known producers of secondary metabolites (polyketides, antibiotics, siderophores, biosurfactants, etc.) and enzymes (amylase, lipase, cellulase, protease), which can be used in pharmaceutical, agricultural, food, pulp and paper, and other industries [9,10,11,12,13,14,15,16,17,18,19]. Of 23,000 bioactive microbial metabolites, about 10,000 metabolites were isolated from actinomycetes [15], among which compounds with herbicidal [20], antitumor [21], antifungal [22], immunomodulating [23,24,25], and other activities were found. Most of the known antimicrobials (streptomycin, streptothricin, actinomycin, etc.) were originally produced by actinomycetes, especially by the genus Streptomyces [26]. Secondary metabolites of actinomycetes are widely used in various human activities and their use will rise in the future (

Table 1. Potential applications of secondary metabolites produced by actinomycetes in various fields of human activities.

Application Area		Review, Book Chapter
Agriculture	Plant growth promoting	[27]
	Phytopathogen control	[28]
	Bioherbicides	[20]
	Biopesticides	[29]
Bioinsecticides	Against insects, mites	[30]
Medicine	Antibiotics	[26,31,32]
	Pharmaceuticals (antitumor, anti-inflammatory, antifungals, antihelminthics, etc.)	[33,34,35,36,37]
	Probiotics	[38,39]
Industry	Detergents (Surfactants)	[40]
	Biofuel	[8]

).

The high biotechnological potential of this group of microorganisms was confirmed by patent analysis (Figure 1), with the largest number of valid patents using actinomycete genera such as Streptomyces, Mycobacterium, Corynebacterium, Bifidobacterium, and Rhodococcus.

Terpene biosynthesis by actinomycetes is an actual research area discussed in research and review publications. However, the specialized reviews are focused on certain genera of actinomycetes and/or groups of terpene derivatives [41,42], bacterial terpenome [43], and evolution and ecology of microbial terpenoids [44]. The present review aims at assessing the biosynthetic potential (via the patent analysis in particular) of various representatives of Actinomycetes as producers of a wide range of biologically active terpenoids, including hybrid metabolites (meroterpenoids). The data can be used to create technologies for the biocatalytic production of practically valuable terpene derivatives using actinomycetes.

In writing this review, various databases were used: scientific articles and reviews were searched through platforms such as Web of Science, Scopus, and NCBI, and WIPO (World Intellectual Property Organization, https://patentscope.wipo.int/, accessed on 25 March 2022) was used to search for patents. To fully cover the topic, the review includes patents and articles (from 2000 to 2022) dedicated to terpene biosynthesis by representatives of Actinomycetes (according to the modern classification).

2. Terpene Biosynthesis by Actinomycetes

Terpene biosynthesis is one of the secondary metabolic pathways in actinomycetes, regulated by biosynthetic gene clusters (BGCs). BGCs include promoters, genes encoding carbon skeleton formation enzymes and post-modification enzymes, and regulatory genes. All terpenes are synthesized from the C5 isoprenoid precursors, namely isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), which are converted to isoprenyl diphosphates of varying lengths by isoprenyl transferases (Figure 2). Further formation of terpenes is catalyzed by a group of enzymes, namely terpene synthases (cyclases) (TSs) catalyzing the cyclization of geranyl (GPP), farnesyl (FPP), geranylgeranyl (GGPP), and geranylfarnesyl (GFPP) diphosphates to yield mono-, sesqui-, di-, sester-, and triterpenes. Unlike the basic biosynthetic enzymes, bacterial TSs have low homology of conserved sequences, providing an extremely diverse group. The main feature of TSs is that one enzyme can produce dozens of hydrocarbon skeletons significantly different from each other. A number of remarkable reviews have been devoted to bacterial and plant terpene synthases [5,6,45,46]. Modification of the terpene skeleton is achieved through the addition of various functional groups mediated by specialized enzymes, mainly those from the cytochrome (P450s) family.

A variety of methods (bioinformatics, genetic, analytical, biochemical, molecular) are employed to study terpene biosynthesis by actinomycetes. Direct screening of compounds from the microbial cultivation medium and their subsequent identification is a basic method of searching for new terpene derivatives; however, it is labor- and time-consuming. Currently, recently developed “genome mining” methods, namely a bioinformatics search for TS genes using the BLAST program and web-based tools such as ClustSCAN, NP.searcher, GNP/PRISM, and antiSMASH, are used to search for actinomycetes capable of producing terpene derivatives. Simultaneous discovery of new compounds and biosynthetic genes and enzymes is one of the most important advantages of the coordinated use of genome analysis and direct analysis of the metabolites. Using this approach, a few dozen terpenes (many of which are unique), several new cyclization mechanisms, and more than 120 putative genes of bacterial terpene synthases have been discovered [47].

Methods of genetic modification (e.g., gene knockout, presumably responsible for the terpene synthesis; editing of individual sections of BGCs, in particular, by introducing additional native or engineered promoters; influence on the regulatory gene expression) and heterologous expression (e.g., cloning of the interest gene in bacteria that are not capable of synthesizing the target product) are used to confirm the functional activity of the studied genes. E. coli or mutant strains Streptomyces avermitilis SUKA 2–22 with deletion of all endogenous BGCs [48], Streptomyces lividans [49], Streptomyces coelicolor, Streptomyces albus, etc. [50,51], can serve as host bacteria. The transformants are used either for the direct terpene synthesis or for the production of recombinant proteins subsequently incubated with acyclic allyl diphosphate substrates. Molecular and biochemical methods allow studying the crystal structure, kinetic and mechanistic parameters of isolated and purified TSs and mechanisms of terpene cyclization [47]. In addition, omics technologies have been actively developed to search for secondary metabolites, terpenoids in particular, to study the diversity, distribution, and evolution of BGCs [52].

2.1. Terpene Derivatives Produced by Streptomycetes and Their Enzymes

The analysis of published data indicates that most of the identified actinomycete terpene derivatives are synthesized by streptomycetes. The spectrum of produced compounds varies from mono- to tetraterpenes and their derivatives.

2.1.1. Mono- and Sesquiterpenes and Their Derivatives

The formation of monoterpenoids as secondary metabolites was registered for individual streptomycetes. Streptomyces clavuligerus ATCC 27064 have been shown to catalyze the formation of monoterpenoids cineole (1, eucalyptol) and linalool (2) [53,54,55]. Heterologous expression of terpene synthases bLinS и bCinS from S. clavuligerus ATCC 27064 in E. coli increased linalool (2) and 1,8-cineole (1) yields to 363 ± 57.9 and 116.8 ± 36.4 mg/L_org, respectively, which exceeded the values obtained using plant enzymes. Furthermore, bLinS catalyzed the nerolidol (3) formation (159.1 ± 71.3 mg/L_org) and acted as a mono- and sesquiterpene synthase (WO2018142109). The use of recombinant bLinS increased the nerolidol (3) and linalool (2) yields to 379 and 1054 ± 245.2 mg/L_org, respectively [56] (WO2020234307; US20210238640). Two new nerolidol-type sesquiterpenoids rel-6R,7R,10R-6,10-epoxy-3,7,11-trimethyldodec-2-ene-1,7,11-triol (4), and rel-6R,7R,10R-7,10-epoxy-3,7,11-tri-methyldodec-2-ene-1,6,11-triol (5) were isolated from S. scopuliridis YIM 32460 [57].

2-Methylisoborneol (6) is an odorous irregular monoterpenoid identified in cultivation medium of some species of streptomycetes [58,59,60,61,62]. Using S. coelicolor A3(2) as an example, the two-gene cluster sco7700/sco7701, whose analogues were identified in S. griseus, S. ambofaciens, and S. scabies, was found to be responsible for 2-methylisoborneol (6) synthesis. Incubation of GPP with recombinant SCO7700A resulted in the production of a complex mixture of cyclic monoterpenes α-pinene (7), β-pinene (23%) (8), limonene (32%) (9), γ-terpinene (29%) (10), δ-terpinene (10%) (11), and trace amounts of monoterpene alcohols [63]. Köksal et al. (2012) determined the crystal structure of 2-methylisoborneol synthase from S. coelicolor A3(2) [64]. This enzyme was found to catalyze the formation of (1R)-(+)-camphor (12) from 2-fluorolinalyl diphosphate [65]. A non-oxidized bicyclic monoterpene 2-methyl-2-bornene (13) was identified among secondary metabolites of S. exfoliatus SMF19 [66].

1	2	3	4
5		6	7	8
9	10	11	12	13

Two homologous genes sc1 и sc2 from S. citricolor NBRC 13005 were involved in the formation of monocyclic sesquiterpenoids (-)-germacradien-4-ol (14) and (-)-epi-α-bisabolol (18) with more than 85% yields [67]. A distinctive feature of germacradien-4-ol synthase is its high specificity and one terpenoid formed as the main product [68]. An uncharacterized TS of S. pratensis ATCC 33331 was identified as (+)-(1(10)E,4E,6S,7R)-germacradien-6-ol synthase and produced compound 19 [69], while terpene synthase Gd11olS from S. coelicolor A3(2) catalyzes FPP cyclization into germacradien-11-ol (15). Computer simulation combined with site-directed mutagenesis of Gd11olS changed the reaction direction with the formation of non-hydroxylated terpene isolepidozene (20) (88%) [70]. Along with the known germacradien-11-ol (15), new monocyclic sesquiterpenoids 1(10)E,5E-germacradiene-3,11-diol (16), 1(10)E,5E-germacradiene-2,11-diol (17), and roseosporol A (21) were identified from S. griseus wild type strain [71] and S. roseosporus Lsr2-deletion mutant strain [72], respectively. 1(10)E,5E-Germacradiene-3,11-diol (16) was detected among the secondary metabolites of S. albolongus YIM 101047 isolated from Elephas maximus feces [73].

Many streptomycetes are characterized by the formation of geosmin (22), a sesquiterpenoid causing a specific smell of moist soil [59,74,75,76]. Microbial methods of geosmin production by S. albus LBG-FXJ (CGMCC 4206), S. fradiae FJ-HX (CGMCC 4205), Streptomyces sp. QC-1 (CGMCC 4535), and Streptomyces sp. QC-2 (CGMCC 4536) have been patented (CN102719376; CN102719375; CN102181392; CN102719377). Genes and enzymes involved in geosmin biosynthesis were studied in the works of Cane et al. (2003–2008). Expression of recombinant protein SC9B1.20 (=SCO6073) from S. coelicolor A3(2) in E. coli resulted in Mg²⁺-dependent transformation of FPP to (4S,7R)-germacra-1(10)E,5E-dien-11-ol (23), a precursor of 22, which indicates that the enzyme belongs to germacradienol/geosmin synthase [75]. Subsequently, germacradienol/germacrene D synthase was shown to be a bifunctional enzyme that, along with 22 (13%) and 23 (74%), catalyzed the formation of (−)-(7S)-germacrene D (24) (10%) and a hydrocarbon (3%) [77,78,79,80], which was later identified as (8S,9S,10S)-8,10-dimethyl-1-octalin (25) [79]. Genes Sav2163 (geoA) and spterp13, analogs of sco6073, were found in S. avermitilis [74] and S. peucetius ATCC 27952 [81], respectively. Incubation of selina-4(15),7(11)-diene synthase from S. pristinaespiralis ATCC 25486 [82] and SAV_76 from S. avermitilis [83] with FPP produced trace amounts of germacrene B (26) and germacrene A (27). Recombinant SpS from S. xinghaiensis S187 catalyzed cyclization of FPP to germacrene D (24), germacrene A (27), and bicyclogermacrene (28) [84]. Germacrene D (24) was also isolated from the culture medium of S. hygroscopicus NRRL 15879 [66].

A new bicyclic sesquiterpenoid (5S,8S,9R,10S)-selina-4(14),7(11)-diene-8,9-diol (29) was produced by Streptomyces sp. QD518 [85]. Crystallographic, functional characteristics, and molecular mechanisms of selina-4(15),7(11)-diene synthase (SdS) from S. pristinaespiralis ATCC 25486 catalyzing the formation of 30 were described [82,86]. Epi-cubenol (31), a bicyclic cadinane sesquiterpenoid, was detected among terpenoids produced by Streptomyces sp. GWS-BW-H5 [53] and S. albolongus YIM 101047 [73]. Overexpression of sgr6065 (gecA) from S. griseus IFO13350 in S. lividans TK21 led to (+)-epi-cubenol (31), while the gecA-knockout mutants lost this ability [87]. In the deuterated growth medium of S. griseus NBRC102592, the unique [2H₂₆]-1-epi-cubenol, firstly obtained by fermentation, was synthesized [88]. Streptomyces sp. JMRC:ST027706 and Streptomyces sp. HKI0595 were isolated from mangrove trees Bruguiera gymnorrhiza and Kandelia candel and produced novel 11-hydroxy- (32), 12-hydroxy- (33) derivatives of 31 and 5,11-epoxy-10-cadinanol (35) [89] and five novel eudesmene-type sesquiterpenoids kandenols A-E (36–40) [90]. Kandenols A (36) and B (37) have a similar structure with plant eudesmenes, while kandenols C (38) and D (39) are unique due to the presence of hydroperoxide fragments. Kandenol E (40) is the first agarofurane isolated from bacteria. The strains S. sanglieri YIM 121209-2 [91], S. anulatus YIM 101882 [92], and Streptomyces sp. RM-14-6 [93] produced new 15-hydroxy-(+)-epi-cubenol (34), 5,11-epoxy-10-cadinanol (35), and isopterocarpolone (41), respectively.

Two new eudesmane-type sesquiterpenoids 1α,6β,11-eudesmanetriol (42) and 11-eudesmene-1α,6β-diol (43) were isolated from Streptomyces sp. YIM 56130 [94]. Along with 42 and 4β,5β,7β,10α-5,11-eudesmanediol (44), S. anulatus YIM 101882 produced new sesquiterpenoids 45–47 and norsesquiterpenoids 48–50 [92]. New norsesquiterpenoids 51–57 were synthesized by Streptomyces sp. 0616208 [95], Streptomyces sp. XM17 [96], and S. albolongus YIM 101047 [73].

As a result of heterologous expression of sscg_02150 and sscg_03688 from S. clavuligerus ATCC 27074 in E. coli, TSs catalyzing the (−)-δ-cadinene (58) and (+)-T-muurolol (59) formation were isolated [97]. Along with (+)-T-muurolol (59) and 3α-hydroxy-T-muurolol (60), two new derivatives of 59, namely 15-hydroxy- (61) and 11,15-dihydroxy (62) derivatives, were obtained from Streptomyces sp. M491 [98].

Purified dauc-8-en-11-ol synthase from S. venezuelae ATCC 10712 was shown to accept non-natural analogues of FPP, such as 10-methyl-FPP, 13-desmethyl-FPP, with the formation of methylated daucenol (64), widdrenol (65); nor-widdrenol (66); tenuifola-2,10-diene (67); and tenuifola-2,11-diene (68). The site-directed mutagenesis of the dauc-8-en-11-ol synthase resulted in a four-fold increase in the biosynthesis efficiency of the target terpenoid 63 [99]. Terpene synthases from S. pristinaespiralis ATCC 25486 [100], S. clavuligerus ATCC 27064, and S. scabiei 8722 [101] catalyzed the formation of (+)-(2S,3S,9R)-pristinol (69), new (+)-intermedeol (70), and (-)-neomeranol B (71), respectively.

14 R1=R2=H, R3=OH, R4=H 15 R1=R2=R3=H, R4=OH 16 R1=R3=H, R2=R4=OH 17 R1=OH, R2=R3=H, R4=OH	18	19	20
21	22	23	24
25	26	27	28
29	30	31 R1=R2=R3=H 32 R1=OH, R2=R3=H 33 R1=R3=H, R2=OH 34 R1=R2=H, R3=OH	35
36 R=H 37 R=OH	38 R=H 39 R=OH	40	41

42		43		44
45	46 R1=OH, R2=R3=H 47 R1=H, R2=R3=OH		48 R1=R2=H, R3=OH 49 R1=OH, R2=R3=H 50 R2=OH, R1=R3=H		51
52	53		54		55 R1=OH, R2=R3=H 56 R1=OH, R2=H, R3=OH 57 R1=H, R2=OH, R3=H

58	59 R1=R2=R3=H 60 R1=OH, R2=R3=H 61 R1=R2=H, R3=OH 62 R2=R3=OH, R1=H	63	64
65	66	67	68
69	70	71

Cheng et al. (2020) studied the ability of streptomycetes to synthesize different volatile terpene derivatives, among which mono-, bi-, and tricyclic sesquiterpenoids were found [66]. S. hygroscopicus NRRL 15879 produced bicyclic sesquiterpenoids β-eudesmol (72), β-vatirenene (73), calamene (74), compound 75, and tricyclic sesquiterpene β-cedrene (76). Additionally, the above strain catalyzed the formation of β-patchoulene (77), dehydro-β-agarofuran (78), and aromadendrene oxide-(2) (79). The monocyclic α-elemol (80), bicyclic sesquiterpene derivatives α-himachalene (81), β-eudesmol (72), α-muurolene (82), and a new 7β-hydroxy-7-epi-α-eudesmol (84) were derived from S. parvulus B1682, S. clavuligerus, S. exfoliatus SMF19, S. aureofaciens ATCC 12551 [66], and S. sanglieri YIM 121209-2 [91], respectively. Three new sesquiterpene synthases from S. chartreusis NRRL 3882 catalyzed the formation of germacradiene-11-ol (15), α-eudesmol (83), and α-amorphene (85) as major products and 10-epi-γ-eudesmol (86) as a minor product [102]. Incubation of recombinant TSs from S. viridochromogenes DSM 40736 with FPP yielded the products identified as 7-epi-α-eudesmol (83) and α-amorphene (85) [103].

Tricyclic humulane sesquiterpenoid (+)-isoafricanol (87) was identified among the volatile metabolites produced by S. violaceusniger Tü 4113. A recombinant (+)-isoafricanol synthase from S. malaysiensis DSM 4137 catalyzed the formation of 87 (95%) and trace amounts of african-1-ene (88) and african-2(6)-ene (89) [104]. Incubation of recombinant SAV_76 of S. avermitilis with FPP in the presence of Mg²⁺ resulted in avermitilol (90), a novel sesquiterpene alcohol, and viridiflorol (91). Transformants of S. avermitilis SUKA17 containing copies of the sav76 gene and the native rpsJp (sav4925) promoter afforded the new ketone avermitilone (92) along with previously obtained compounds [83].

72	73	74	75
76	77	78	79
80	81	82	83 R=H 84 R=OH
85	86	87	88
89	90	91	92

Tricyclic sesquiterpene β-caryophyllene (93) was identified among the volatile organic compounds produced by S. yanglinensis 3-10 [62]. The formation of (+)-caryolan-1-ol (94), an oxidized derivative of β-caryophyllene (93), was observed during the cultivation of wild-type or genetically modified strains of streptomycetes [73,105,106,107] (WO2018062668). Along with known 9α-hydroxy- (95), 9β-hydroxy- (96), novel 7α-hydroxy- (97), 10-hydroxy- (micaryolane A) (98), and 15-hydroxy- (micaryolane B) (99) derivatives of 94 were isolated from Streptomyces sp. YIM 56130 [94], Streptomyces sp. AH25 [108], S. anulatus YIM 101882 [92], and S. albolongus YIM 101047 [73]. Bacaryolanes A-C (100–102), enantioisomers of plant caryolans, were separated from the fermentation broth of Streptomyces sp. JMRC:ST027706 [109] and S. anulatus YIM 101882 [92].

Epi-isozizaene (103), tricyclic sesquiterpene, was generated by several Streptomyces species and initially sparked interest as a candidate jet fuel on account of having a specific energy similar to that of jet fuel A-1 [110,111]. Heterologous epi-isozizaene synthase from S. coelicolor A3(2) and pentalenene synthase from Streptomyces sp. UC5319 produced 103, pentalenene (107) and α-isocomene (108) [111]. Using the genetic engineering techniques increased the yields of 108, 103, and 107 in E. coli to 77.5 mg/L, 727.9 mg/L, and 780.3 mg/L, respectively, while the yield of 107 was improved to 344 mg/L in Saccharomyces cerevisiae (US20200239796).

Epi-isozizaene synthase (sco5222) of S. coelicolor A3(2) catalyzed multi-step cyclization of FPP to 103, which is oxidized by P450 (sco5223) to albaflavenone (109), a broad-spectrum antibiotic [112,113,114], detected in the culture medium of some species of streptomycetes [115,116,117]. Genome-wide analysis of S. spectabilis NRRL-2792 found the albaflavenone biosynthetic gene cluster [118]. S. avermitilis SUKA16 transformant, which expresses sav3032 (ortholog sco5222) and promoter rpsJp (sav4925) from the native strain S. avermitilis, accumulated 103, (4R)-albaflavenol (104), (4S)-albaflavenol (105), albaflavenone (109), and a new compound 4β,5β-epoxy-2-epi-zizaan-6β-ol (110) [119]. New sesquiterpenoids identified as albaflavenol B (106) and albaflavenoid (111) were isolated from Streptomyces sp. Lv-4-26 [120] and S. violascens YIM 100225 [121], respectively.

Twenty-six site-directed mutants of the S. coelicolor A3(2) epi-isozizaene synthase catalyzed the formation of acyclic (119–121), mono- (122–125), bi- (126–130), and tricyclic (110, 83, 131–135) sesquiterpenes, which makes this enzyme a universal platform for obtaining various terpene derivatives [110,122] (WO2015120431). New tricyclic sesquiterpenoids strepsesquitriol (136) and bungoene (137) were obtained from Streptomyces sp. SCSIO 10355 [123] and S. bungoensis DSM 41781 [124], respectively.

93	94 R=H 95 R1=H, R2=αOH 96 R1=H, R2=βOH 97 R1=αOH, R2=H	98 R1=OH, R2=H 99 R2=OH, R1=H	100
101 R=αH 102 R=βH	103 R1=R2=H 104 R1=αOH, R2=H 105 R1=βOH, R2=H 106 R1=αOH, R2=OH	107	108
109	110	111	112
113	114	115	116
117	118	119	120
121	122	123	124
125	126	127	128
129	130	131

Pentalenolactone (132) is a tricyclic sesquiterpenoid antibiotic, derived from pentalenene (107) and synthesized by more than 30 Streptomyces species. The resistance of streptomycetes to 132 was found to be determined by the gap1 gene (sav2990). Pentalenene synthase was first isolated from S. exfoliatus UC5319 in the 1990s. Exemplified by S. avermitilis, S. exfoliatus UC5319, and S. arenae TÜ469, the metabolic pathways of pentalenolactone synthesis were studied. The 13.4 kb BGC comprising 13 unidirectionally transcribed open reading frames (ORFs) (sav2990–sav3002) was shown to be responsible for the pentalenolactone (132) synthesis. The cyclization of FPP to 107 is catalyzed by PtlA (sav2998) [125]. Its further oxidation involves PtlI (sav2999) with the formation of 1-deoxypentalen-13-ol (133), 1-deoxypentalen-13-al (134), and 1-deoxypentalenic acid (136) [126], while its oxidation with PtlH hydroxylase (sav2991), PtlF dehydrogenase (sav2993) and PenD, PntD, or PtlD resulted in the formation of (-)-11β-hydroxy-1-deoxypentalic acid (137) [127], 1-deoxy-11-oxopentalenic acid (138) [128], and pentalenolactones D (140), E (141) and F (142) [129], respectively. The penM and pntM genes were found to be responsible to final step in pentalenolactone biosynthesis [130]. Pentalenolactone biosynthesis in S. exfoliatus UC5319 and S. arenae TÜ469 is regulated by the orthologous proteins PenR and PntR [131]. Jiang et al. (2009) described a new direction of the pentalenolactone biosynthetic pathway involving the oxidation of 138 by PtlE (sav2994) to neopentalenolactone D (143), and its subsequent conversion to neopentalenolactone E (144), compound PL308 (145), hydroxyl derivatives (139) and (146), an oxidized lactone (147), and seco-acids 148 and 149 [132].

Pentalenic acid (135), a co-metabolite of 132 and 143, is formed due to the oxidation of 136 by cytochrome CYP105D7 (sav7469) [133]. Genome-wide analysis of Streptomyces sp. NRRL S-4 identified a biosynthetic cluster of pentalenolactone type terpenes: 1-deoxy-8α-hydroxypentalic acid (150) and 1-deoxy-9β-hydroxy-11-oxopentalenic acid (151) [134].

132	133 R1=H, R2=CH2OH 134 R1=H, R2=CHO 135 R1=OH, R2=COOH	136 R=H 137 R=OH	138 R=H 139 R=OH
140	141	142	143
144	145	146	147
148 R=H 149 R=OH	150	151

The S. avermitilis SUKA22 transformant with sclav_p1407 afforded eight sesquiterpenes, with the tricyclic isohirsut-1-ene (cucumene, 152) being the main product. With that, slt18_1880 of S. lactacystinaeus OM-6159 was responsible for the formation of isohirsut-4-ene (153). Isohirsut-1-ene (152) and isohirsut-4-ene (153) are linear triquinane sesquiterpenes that have never been isolated from bacteria or any other source before [135] (WO2015022798). Using computer modeling, cucumene synthase B5GLM7, the first TS involved in the synthesis of linear triquinane, was identified in S. clavuligerus ATCC 27604 [136], and its crystal structure was later described [137]. The recombinant sesquiterpene synthase from S. lincolnensis NRRL 2936A produced a novel tetracyclic sesquiterpene isoishwarane (154) with a unique structure [138].

The recombinant SpS from S. xinghaiensis S187 converted 10,11-dehydro-FPP into sesquiterpenes isopentylkelsoene (157) and spat-13-ene (161). Moreover, it transformed GGPP into new diterpenes prenylkelsoene (155), spata-13,17-diene (158), cneorubin Y (159), and GFPP into new sesterterpenes geranylkelsoene (163) and prenylspata-13,17-diene (160). This reaction features of SpS proved that this TS exhibited sesqui-, di-, and sesterterpene synthase activity [84].

152	153	154	155 R=prenyl 156 R=geranyl 157 R=ipent
158	159 R=prenyl	160 m=0, n=2 161 m=1, n=0

2.1.2. Diterpenes and Their Derivatives

Two unique terpene cyclases DtcycA and DtcycB from Streptomyces sp. SANK 60404 were described as responsible for the formation of cembrene C (162), (R)-nephthenol (163), (R)-cembrene A (164), and a new compound identified as (4E,8E,12E)-2,2,5,9,13-pentamethylcyclopentadeca-4,8,12-trien-1-ol (165) [139].

Co-cultivation of S. cinnabarinus PK209 with Alteromonas sp. KNS-16 induced the formation of a diterpenoid lobocompactol (166) [140]. The ability of streptomycetes to synthesize new eunicellane-type diterpenoids was proved. Streptomyces sp. CL12-4 [141] and S. albogriseolus SY67903 [142] produced unique benditerpenoic acid (167) and microeunicellols A (168), B (169), respectively. Enzymatic and mechanistic characteristics of the benditerpenoic acid synthase from Streptomyces sp. CL12-4 were described in the article [143].

162	163	164	165
166	167	168		169

The transformants of S. avermitilis SUKA22 containing CldD/CldB, CldB/SCLAV_p0490, SCLAV_p0490/CldD, and SCLAV_p0490/SCLAV_p0491 genes of diterpene synthases from S. clavuligerus ATCC 27064 produced labdane-type diterpenoids. The diterpene derivatives were identified as labda-8(17),12(E),14-triene ((E)-biformene, 170), labda-8(17),13(16),14-triene (172), ladba-7,12(E),14-triene (173), and a new compound labda-7,13(16),14-triene (174) [144]. Centeno-Leija et al. (2019) described the X-ray crystal structure of (E)-biformene synthase isolated from S. thermocarboxydus K155 for the first time. The (E)-biformene synthase was encoded by the LrdC, which was identified as part of the LRD cluster [145,146]. Transformants of S. coelicolor M1152, S. peucetius var. caesius and S. avermitilis SUKA22 having the LRD cluster generated 170 [147]. Streptomyces sp. KIB 015 produced four new labdane-type diterpenoids, labdanmycins A–D (175–178), while the labE gene deletion led to the formation of raimonol (171), their biogenetic precursor [148]. The formation of compound 171 was also observed upon insertion of the rmn cluster from S. anulatus GM95 to S. avermitilis SUKA22. The transformants S. avermitilis SUKA22 [149] and S. cyslabdanicus K04-0144Δcld [147] containing the cld or lrdABDC clusters produced (7S,8S,12E)-8,17-epoxy-7-hydroxylabda-12,14-diene (179).

The diterpene synthase Stt4548 from Streptomyces sp. PKU-TA00600 catalyzed the normal-copalyl diphosphate (CPP) cyclization to isopimara-8(9),15-diene (180) [150]. Both strains Streptomyces sp. KO-3988 [151] and Streptomyces sp. SN194 [152] synthesized diterpenoid 3-hydroxypimara-9(11),15-diene (viguiepinol, 181) via the formation of ent-CPP (183) and pimara-9(11),15-diene (182) as intermediates.

170 R=H 171 R=OH	172	173	174
175 R=H 176 R=OH	177 R1=H, R2=CH2OH 178 R1=OH, R2=CH3	179	180
181 R=OH 182 R=H	183

The biosynthetic cluster responsible for synthesis of tricyclic diterpenoid cyclooctatin (184) was found in S. melanosporofaciens MI614-43F2. This cluster consists of four genes, cotB1-cotB4, encoding GGDP synthase, CotB2 terpene cyclase, and two P450 cytochromes. The incubation of recombinant CotB2 with GGDP resulted in the formation of cyclooctat-9-en-7-ol (187) [153]. Later, the crystal structure and mechanistic characteristics of CotB2 were described [154,155,156,157]. A mutant of diterpene synthase CotB2 (W288G) was found to produce (1R,3E,7E,11S,12S)-3,7,18-dolabellatriene (188), but not the native product 187 [158]. Recombinant E. coli carrying the CotB3 or CotB4 duet vector in combination with AfR-Afx gene cassettes from S. afghaniensis produced 184 with a 43-fold increase (up to 15 mg/L) compared with the native producer. Moreover, CotB3 was found to be able to hydroxylate (−)-casbene (189) to form sinularcasbane D (190) [159]. New 16,17-dihydroxy- (185) [160], 17-hydroxy- (186) [161,162] and 18-acetyl- (191), 5-dehydroxy- (192), and 5,18-dedihydroxy- (193) [163] derivatives of 184 were isolated from Streptomyces sp. LZ35, Streptomyces sp. MTE4a, Streptomyces sp. M56, and Streptomyces sp. ZZ820, respectively. Three new fusicoccane-type diterpenoids, 12α-hydroxy- (194), 12β-hydroxy- (195), and 14-hydroxycyclooctatin (196), were separated from the fermentation broth of S. violascens YIM 100212 isolated from the feces of Ailuropoda melanoleuca [164]. The formation of new tricyclic diterpene lydicene (197) was observed using the recombinant TS StlTC, with unique UbiA-type diterpene cyclases, from S. lydicus [165].

184 R1=R2=CH3 185 R1=R2=CH2OH 186 R1=CH3, R2=CH2OH	187	188	189 R=H 190 R=βOH
191 R1=OH, R2=COCH3 192 R1=R2=H	193	194 R1=αOH, R2=H 195 R1=βOH, R2=H 196 R1=H, R2=αOH	197

Genome mining of S. venezuelae ATCC 15439 revealed ven, a silent biosynthetic cluster responsible for the synthesis of diterpenoids venezuelaenes A (198) and B (5-oxo-venezuelaene A) (199) with a unique 5-5-6-7 tetracyclic skeleton [166]. Rabe et al. (2017) performed a mechanistic study of two diterpene cyclases, spiroviolene synthase from S. violens NRRL ISP-5597 and tsukubadiene synthase from S. tsukubaensis NRRL 18488, which catalyze the formation of 200 and 201. Although the structures of 200 and 201 are significantly different, the cyclization mechanisms of both enzymes proceed through the same initial cyclization reactions, which proved their phylogenetic similarity [167,168]. The generation of a new tetracyclic diterpene cattleyene (202) was observed using the recombinant TS CyS from S. cattleya NRRL 8057 [169].

198	199	200
201	202

Based on the large-deletion mutant S. avermitilis SUKA22, the transformants catalyzing the formation of terpene derivatives with various structures were created. The expression of sclav_p1169 and sclav_p0765 from S. clavuligerus ATCC 26074 led to the formation of monocyclic prenyl-β-elemene (203), prenylgermacrene B (204), bicyclic clavulatriene A (205), clavulatriene B (206) or bicyclic isoelisabethatriene B (207), tetracyclic hydropyrene (208), and hydropyrenol (209). The transformant carrying slt18_1078 from S. lactacystinaeus OM-6159 catalyzed a tricyclic diterpene cyclooctat-7(8),10(14)-diene (210). The stsu_20912 gene from S. tsukubaensis NRRL 18488 was responsible for the synthesis of 201, while the transformant with nd90_0354 from Streptomyces sp. ND90 synthesized tricyclic odyverdienes A (211) and B (212). The derived diterpenoids are novel compounds with unique hydrocarbon skeletons [135] (WO2015022798). Under normal conditions, a hydropyrene synthase from S. clavuligerus ATCC 27064 produced hydropyrene (208, up to 52%) and hydropyrenol (209, up to 26%), and minor amounts of isoelisabethatrienes A (213) and B (207), biosynthetic precursors of pseudopterosins with pronounced anti-inflammatory activity. An increase in the yield of 213 and 207 to 41.91 ± 1.87 mg/L was achieved using a genetically modified hydropyrene synthase [170] (WO2022003167).

203	204		205
206	207	208		209
210	211	212		213

2.1.3. Sester-, Tri-, and Tetraterpenes and Their Derivatives

Unlike sesqui- and diterpenes, the formation of terpene derivatives with a chain length of more than 20 carbon atoms was observed only for individual strains of Streptomycetes. Sesterterpene cyclases were isolated from S. somaliensis ATCC 33201™ and S. mobaraensis NBRC 13819 (=NRRL B-3729) and generated new somaliensenes A (214) and B (215) [171], sestermobaraenes A–F (216–221), and sestermobaraol (222) [172], respectively.

214			215
216	217			218
219	220			221
222

The heterologous expression of hopA and hopB (encoding squalene/phytoene synthases) and hopD (encoding farnesyl diphosphate synthase) from S. peucetius ATCC 27952 in E. coli provided an acyclic triterpene squalene (230) with a yield of 11.8 mg/L [173]. Another acyclic triterpene, botryococcene (231), was produced by activating the Fur22 regulator and simultaneous expression of the biosynthetic genes of S. reveromyceticus SN-593. The yield of the target product was 0.3 g/L, which is comparable to the levels of other microbial producers [174].

Hopanoids are unusual pentacyclic triterpenes present in bacterial species. Hop-22(29)-ene (290) was isolated from wild-type [175,176] and genetically modified strains of streptomycetes [72,177]. A genome-wide analysis of S. scabies 87–22 detected a hopanoid biosynthetic cluster responsible for the synthesis of 232 [178]. The squalene-hopene cyclase (spterp25) catalyzing the complex cyclization of 230 to the pentacyclic triterpene 232 was described for S. peucetius ATCC 27952 [179].

223	224
225

2.1.4. Hybrid Metabolites (Meroterpenoids)

Meroterpenoids are products of mixed biosynthetic origin that consist of terpenoid scaffold combined with polyketide, alkaloid, phenol, or amino acid. According to their different biosynthetic origins, meroterpenoids can be divided into two groups, polyketide and non-polyketide terpenoids. Meroterpenoids have attracted researchers’ attention due to their unusual chemical structures and a wide range of biological properties [180].

Naphthoquinone-based meroterpenoids are large chemically diverse group including napyradiomycins, merochlorins, marinones, furaquinocins, etc., some of which have a high therapeutic potential. Naphthoquinone-based meroterpenoids derived from streptomycetes are described in the review published in 2020 [181], so our review highlights the most active producers and the derivatives with promising biological activity, as well as compounds isolated after 2020.

Biosynthesis of naphthoquinone-based meroterpenoids includes regioselective addition of aromatic polyketide (1,3,6,8-tetrahydroxynaphthalene) to a terpene diphosphate catalyzed by ABBA prenyltransferase (PTase). After the initial prenylation, oxidation, halogenation and cyclisation steps occur. Genome mining of streptomycetes as producers of naphthoquinone-based meroterpenoids led to the discovery of unique prenyltransferase and vanadium-dependent haloperoxidase (VHPO) enzymes, which differ significantly from those previously described for algae and fungi [182,183]. For instance, the high-resolution crystal structures of two homologous members of the VHPO family associated with napiradiomycin biosynthesis, NapH1 and NapH3, were characterized [184].

Furaquinocins A (226) and B (227) were first isolated from the culture broth of Streptomyces sp. KO-3988 [185] and Streptomyces sp. strain CLl 90 (WO2006081537). Later, analogues of these compounds (228–231, 234, 235) [186] and the fur cluster responsible for furaquinocin biosynthesis were determined [187]. Among secondary metabolites derived from Streptomyces sp. TBRC7642 new furaquinocin I (232), streptolactone (239) and previously identified furaquinocins B (227), D (229), and murayaquinone (240) were described [188]. Furaquinocins I (232), J (233), JBIR-136 (236), and furaquinocins K (237) and L (238) were obtained from genetically engineered S. reveromyceticus SN-593 [189], Streptomyces sp. 4963H2 [190], and Streptomyces sp. Je 1-369 [191].

Streptomyces sp. CNH-189 produced unique halogenated meroterpenoids, merochlorins A–J (241–250) and meroindenon (251) [192,193,194], of which biosynthesis determined the presence of mcl gene cluster with VHPO genes [182]. Flaviogeranin A (252) is promising neuroprotective agent produced by Streptomyces sp. RAC226 [195]. Along with 252, six flaviogeranin congeners or intermediates (253–258), including novel flaviogeranins B1 (255), B (253), containing an amino group, and flaviogeranin D (256), were derived from Streptomyces sp. B9173 [196].

								R1	R2	R3
						226		OH	CH3	OH
						227		OH	CH2OH	H
						228		H	CH3	H
						229		OH	CH3	H
						230		H	CH2OH	H
						231		OH	CH2OH	OH
						232		OH	COOH	H
						233		OH	CONH2	H
234						235
236				237
238		239					240
241		242					243
244			245 246
247			248 R=OH 249 R=Cl
250			251
252			253
254	255				256
257	258

Naphthoquinone-based meroterpenoids naphterpin (259) and related compounds (260–263) were produced by Streptomyces sp. CNQ-509 and Streptomyces sp. CL190 (WO2006081537) and displayed pronounced antioxidant effect [197,198,199]. The napyradiomycins are a large group of unique meroterpenoids with different halogenation patterns and a monoterpenoid subunit attached to C10a. Napiradiomycins were first isolated from Chainia rubra in 1986 (later transferred to the genus Streptomyces), and more than 50 analogous compounds have been identified to date. They have been arranged into three main types according to their structural features: Type A with a linear terpene chain; Type B with the side chain cyclized to a cyclohexane ring; and Type C with monoterpenoid subunit cyclized between C7 and C10a of the naphthoquinone core to form a 14-membered ring.

259	260 R=βOH 261 R=αOH	262 R=H 263 R=COCH3

Among napyradiomycins produced by Streptomyces sp. YP127 [200], Streptomyces sp. CA-271078 [201], S. antimycoticus NT17 [202,203], and Streptomyces sp. SCSIO 10428 [204], biologically active napyradiomycin A1 (264) and its Br-containing (266) derivative were isolated. Chemical analysis of a crude extract of Streptomyces sp. YP127 detected a series of napyradiomycins, in particular 16Z-19-hydroxynapyradiomycin A1 (265) possessed the high anti-inflammatory and antioxidant activities [205]. Along with 264, Streptomyces sp. CNQ-329, CNH-070 [206], and Streptomyces sp. SCSIO 10428 [204] produced napyradiomycins B type 273, 274, 275, 284, and the later strain also catalyzed the formation of bicyclic naphthomevalin (289). Napyradiomycins of A (265, 269) and B (275) types as well as SF2415B3 (269), A80915A (277) carrying additional methyl group at C7 and their 4-dehydro-4a-dechloro- (270, 276, 282) derivatives were isolated from S. aculeolatus PTM-029 and PTM-420 [207]. Streptomyces sp. CNQ-525 produced antibacterial or cytotoxic napyradiomycins 277, 280–283 [208] and Br-containing 271 [209]. Napyradiomycins 7-demethyl SF2415A3 (272) and 7-demethyl A80915B (285) containing diazonium group as well as R-3-chloro-6-hydroxy-8-methoxy-α-lapachone (286) were derived from S. antimycoticus NT17 [202]. Napyradiomycin D1 (287) was derived from Streptomyces sp. CA-271078 [203] and displayed an unprecedented 14-membered cyclic ether ring between the prenyl side chain and the chromophore, thus representing the first member of a new type of napyradiomycins. The biosynthetic methods for obtaining of napyradiomycins A1 (264), B1 (273), A4 (267), A80915H (290), A80915G (291), naphthomevalin (289) by S. kebangsaanensis WS-68302 (CN114805278); A80915A (277), A80915B (278), A80915D (279), A80915G (291) by S. aculeolatus A80915 (NRRL 18422) (EP0376609); and 3-dechloro-3-bromonapyradiomycin A1 (266) by Streptomyces sp. SCSIO 10428 (CN105399721) were patented.

Four new sesquiterpene naphthoquinones, marfuraquinocins A–D (292–295), were isolated from the fermentation broth of S. niveus SCSIO 3406 [210].

Teleocidin B (296) is a well-known naturally occurring tumor promoter. Since the isolation of 296 in the early 1960s [211], more than 44-related compounds have been isolated. In many cases, these compounds have a monoterpene moiety. Biosynthesis of the teleocidin-type indole alkaloids and enzymatic reactions of teleocidin B biosynthesis are summarized in the reviews [212,213,214]. More recent investigation of Streptomyces sp. CNQ766 led to the identification of an unusual meroterpenoid azamerone (297), which has an unprecedented chloropyranophthalazinone core with a 3-chloro-6-hydroxy-2,2,6-trimethylcyclohexylmethyl side chain [215]. Along with known bacterial metabolites WS-9659A14 (lavanducyanin, 304) and the C-2 chlorinated analog WS-9659B14 (305), marinocyanins A–F (298–303) were isolated from Streptomyces sp. CNS-284 and CNY-960. Marinocyanins represent first bromo-phenazinones with an N-isoprenoid substituent in the skeleton [216].

Farnesides A (306) and B (307), new sesquiterpene nucleosides, were isolated from Streptomyces sp. CNT-372 [217]. Two new geranylated phenazines, phenaziterpenes A (308) and B (309), were isolated from the fermentation broth of S. niveus SCSIO 3406 [210]. Subsequent genome analysis of this strain revealed the presence of a BGC encoding enzymes necessary for the biosynthesis of 292–295, 308, and 309 [218].

264	265	266
267	268	269
270	271	272
273 R=Cl 274 R=Br	275 R=Cl 276 R=Br	277
278	279	280
281	282	283
284	285	286
287	288
289	290 R1=OH, R2=CH2OH 291 R1=H, R2=CH3
292 R1=βCH3, R2=H 293 R1=αCH3, R2=H 294 R1=βCH3, R2=OH 295 R1=αCH3, R2=OH	296	297
298 R1=R2=H, R3=H 299 R1=R2=H, R3=OH 300 R1=OH, R2=H, R3=H 301 R1=H, R2=OH, R3=H	302	303
304 R=H 305 R=Cl	306
307

Xiamycin A (310) and its methyl ester (311) were obtained from Streptomyces sp. GT2002/1503 and Streptomyces sp. SCSIO 02999 [219,220]. Xiamycin represents one of the first examples of indolosesquiterpenes isolated from prokaryotes [221]. BGC responsible for xiamycin biosynthesis (xia), key enzymes and intermediates preindosespene (314), indosespenol (315), 316, 317, indosespene (318) were determined and described in [219,222,223,224] (CN102732534). Xiamycins C–E (323, 324, 321) and xiamycin B (313), 318, and sespenine (319), along with 310, were isolated from the culture broth of a Streptomyces sp. HK18 [225] and Streptomyces sp. HKI0595 [226], respectively. New indolosesquiterpenes oridamycins A (326) and B (327) were identified from Streptomyces sp. KS84 [227]. Along with 310 and oxiamycin (320), Streptomyces sp. SCSIO 02999 catalyzed the formation of dixiamycins A (328), B (330), and chloroxiamycin (312). Compounds 328 and 330 represent the first examples of atropoisomerism of naturally occurring N-N-coupled atropo-diastereomers [220] (CN102757908). Genome mining of S. xinghaiensis NRRL B-24674T resulted in the discovery of nine xiamycin analogs, including three novel compounds 19-methoxy-xiamycin (325), 19-carbonyl-xiamycin (322), and 19-hydroxy-24-methyl ester-N-N-dixiamycin (329) [228]. Two new compounds 331 and 332, along with known dixiamycins (333–337, 340), were derived from S. olivaceus OUCLQ19-3 [229]. Biocatalytic production of bixiamycins (333/334, 335/336, 337) and sulfonylbixiamycins (338–340) using S. albus transformant with xia from Streptomyces sp. SCSIO 02999 was patented, wherein a key role of flavin-dependent enzyme (XiaH) in biosynthesis of sulfadixiamycins, unprecedented sulfonyl-bridged alkaloid dimers, was proved [230,231] (WO2014029498).

The strain Streptomyces sp. K04-0144, representing a novel species S. cyslabdanicus (=NBRC 110081T, DSM 42135T) [232], catalyzed the formation of the N,S-containing labdane diterpenoid cyslabdan A (341) and its 18-hydroxy- (cyslabdan B, 342) and 1’-methoxy- (cyslabdan C, 343) derivatives [233]. Genome-wide analysis of S. cyslabdanicus K04-0144 revealed the cld cluster consisting of the cldA, cldB, cldC, and cldD genes responsible for cyslabdan biosynthesis. The transformants of S. avermitilis SUKA22 containing the cld cluster produced 341 as well as its new 17-hydroxy- (344) and 2α-hydroxy- (345) derivatives, and (7S,8S,12E)-8,17-epoxy-7-hydroxylabda-12,14-diene (346). Insertion of the cld-like rmn cluster from S. anulatus GM95 in S. avermitilis SUKA22 resulted in raimonol (171) [149]. In addition, the heterologous expression of the lrdABDC cluster from S. thermocarboxydus K155 in the S. cyslabdanicus K04-0144Δcld mutant led to the formation of 341 and 346 [147].

Streptomyces sp. KO-3988 [234], S. griseus CB00830 [235], and Streptomyces sp. SN194 [152] synthesized novel oxaloterpins A–E (347–351). Two new Cl-containing diterpenoids chloroxaloterpins A (352) and B (353) containing unique groups [(2-chlorophenyl)amino]carbonyl and 2-[(2-chlorophenyl)amino]-2-oxo-acetyl, respectively, were identified among the metabolites of Streptomyces sp. SN194 [152].

308 R=H 309 R=CH3	310 R1=R2=R3=H 311 R1=R2=H, R3=CH3 312 R1=H, R2=Cl, R3=H 313 R1=OH, R2=R3=H		314 R=H 315 R=CH2OH 316 R=CH(OH)2 317 R=CHO 318 R=COOH
319	320		321 R=CH3 322 R=H
323 R1=H, R2=αOH, R3=H 324 R1=H, R2=αOH, R3=CH3 325 R1=H, R2=OCH3, R3=H		326 R=CH3 327 R=CH2OH
328 R=H 329 R=CH3		330 dixiamycin B
331		332
333		334
335		336
337		338
339		340
341 R1=R2=H, R3=CH3, R4=H 342 R1=R2=H, R3=CH2OH, R4=H 343 R1=R2=H, R3=R4=CH3 344 R1=H, R2=OH, R3=CH3, R4=H 345 R1=OH, R2=H, R3=CH3, R4=H		346

	347 R=	348 R=	349 R=
	351 R=NH2
350 R=		352 R=	353 R=

Streptomyces sp. Tü6071 produced phenalinolactones A–D (354–357), tricyclic terpene glycosides, and their derivatives 359–362, 365, and 366 [236,237]. The mutants of Streptomyces sp. Tü6071 with inactivated oxygenase genes (plaO2, plaO3, plaO5), dehydrogenase genes (plaU, plaZ) and putative acetyltransferase gene (plaV) yielded phenalinolactone derivatives PL HS2 (364), PL X1 (363) PL HS6 (367), and PL HS7 (368) [238]. Later, the intermediates of synthesis of phenalinolactones A (354) and D (357) were identified as PL IM1 (370) and PL IM2 (369), respectively [239]. Heterologous expression of the phenalinolactone BGC (35 genes) in S. coelicolor M512 resulted in the formation of the non-glycosylated derivative phenalinolactone E (358) [240].

Tiancilactones A–K (371–381), close structural analogues of phenalinolactones, were discovered by genome mining of diterpene synthases in Streptomyces sp. CB03234 and Streptomyces sp. CB03238. Tiancilactones are characterized by a highly functionalized diterpene backbone, which comprises chloroanthranilate and γ-butyrolactone moieties, and exhibit antibacterial activity [241]. Two new terpenoids with unique a 6-6-6-fused ring system and an oxidized unsaturated γ-lactone, namely trinulactones A (382) and B (383), were isolated from Streptomyces sp. S006 [242].

	R1	R2	R3		R4
354	OH	-CO-CH3			CH3
355	OH	-CO-CH3			H
356	OH	-CO-CH3			-CH2-O-CH3
357	H	-CO-CH3			CH3
358	H	-CO-CH3	OH		CH3
359	H	-CO-CH3			CH3
360	H	H	H		CH3
361	H	-CO-CH3	H		CH3
362	H	H	OH		CH3
363	H	H			CH3
364	H	-CO-CH3			-CH2-O-CH3
						367 R=αOH
						368 R=O
365 R=αOH 366 R=O						369 R
370				371 R1=Cl, R2=CH3, R3=OCH3 372 R1=H, R2=CH3, R3=OCH3 373 R1=Cl, R2=CH3, R3=OH 374 R1=Cl, R2=CH3, R3=oxo 375 R1=Cl, R2=H, R3=OCH3
376				377
378				379 R=H 380 R=CH3
381 R=H 382 R=OH				383

Fusicomycin A (384), its isomer 385, and fusicomycin B (386) were separated from the fermentation broth of S. violascens YIM 100212 [164]. Two new non-cytotoxic diterpene streptooctatins A (387) and B (388) were obtained from Streptomyces sp. KCB17JA11 [243]. Actinoranone (389) is new meroterpenoid derived from Streptomyces sp. CNQ-027 consisting of an unprecedented dihydronaphthalenone polyketide linked to a bicyclic diterpenoid [244].

		384 R=	385 R=		386 R=
387	388			389

S. platensis MA7327 and S. platensis MA7339 were shown to synthesize platensimycin (390) and platencin (391), representatives of a new class of broad-spectrum antibiotics against Gram-positive bacteria, in particular S. aureus [245,246]. Further study proved the involvement of ent-kaurene and ent-atiserene synthases in biosynthesis of 390 and 391, representing a new biosynthetic pathway for diterpenoids [247,248,249]. The crystal structure of PtmT2, an ent-copalyl diphosphate synthase involved in the biosynthesis of 390 and 391 in S. platensis CB00739, was described. PtmT2 catalyzed the cyclization of GGPP to ent-CPP, which subsequently channeled into (16R)-ent-kauran-16-ol (392) or ent-atiserene (393) by two distinct type (canonical or UbiA-type) diterpene synthases specific for biosynthesis of 390 or 391, respectively [250]. The metabolically engineered strains S. platensis SB12002 and SB12600 produced 390 and 391 with yields of 323 ± 29 mg/L and 255 ± 30 mg/L, respectively, hundreds of times greater than those of wild-type strains [251,252] (US20090081673). S. platensis SB12600, in addition to 391, accumulated eight new congeners, platencins A2–A9 (394–402) [253]. A method for obtaining 390 using the mixed culture of S. hygroscopicus HOK021 (NITE P-02560) and Tsukamurella pulmonis TP-B0596 was patented (JP2019149945). Exemplified by 390 and 391, a method of searching for novel natural compounds based on the analysis of biosynthetic genes was proposed (WO2015200501). Data on the biosynthesis features and biological activity of natural and synthetic analogues of platensimycin and platencin were summarized in the reviews [254,255].

The intermediates of hopanoids biosynthesis, N-containing aminobacteriohopanetriol (403), and adenosylhopane (405), as well as bacteriohopanetetrol (404) and ribosylhopane (406), were determined. Orf14 and orf18 of S. coelicolor A(3)2 responsible for the synthesis of 403 were identified [176].

Among the secondary metabolites of Streptomyces sp. YIM 56130, triterpene glycoside soyasaponin I (407) [94] with a wide spectrum of biological activities [256] was obtained. The tetraterpene glycoside KS-505a (longestin, 408) produced by S. argenteolus A-2 (FERM BP2065) has a unique structure consisting of a tetraterpene skeleton with 2-O-methylglucuronic acid and O-succinyl benzoate moieties [257].

390	391			392
393	394 R1=OH, R2=H 395 R1=H, R2=OH
396 R1= R2=H 397 R1=OH, R2=H 398 R1=H, R2=OH				399 R=OH
400			401 R=SCH3 402 R=OCH3
		403 R=NH2 404 R=OH		405
406
		407
408

2.2. Terpene Derivatives Produced by Others Actinomycetes and Their Enzymes

Although most of the found actinomycete terpene derivatives are synthesized by streptomycetes, there is an increasing number of publications on terpene biosynthesis by representatives of the genera Nocardiopsis, Amycolatopsis, Isoptericola, Saccharopolyspora, Salinispora, Kitasatosporia, Verrucosispora, etc. The compounds produced are represented mainly by sesqui- and diterpenes and their derivatives.

2.2.1. Mono- and Sesquiterpenes and Their Derivatives

Among the secondary metabolites of Nocardiopsis chromogenes YIM 90109, two new monocyclic germacradiene-type sesquiterpenoids germacradiene-9β,11-diol (409) and 11-hydroxy-germacradien-2-one (2-oxygermacradienol, 410) were identified along with the known geosmin-type sesquiterpenoid 46 [258]. The TSs from Kitasatospora setae KM-6054 [259] and Micromonospora marina DSM 45555 [260] catalyzed the formation of hedycaryol (411) and (−)-germacrene A (27), respectively. The ability to produce bicyclic 2-methylisoborneol (6) and geosmin (22) was described for Nocardia cummidelens and N. fluminea [59]. The transformant of S. avermitilis carrying the genes from Saccharopolyspora erythraea NRRL2338 yielded 2-methylisoborneol (6), while Micromonospora olivasterospora KY11048 synthesized 2-methyleneornane (412) [58].

409	410	411	412

Two new monocyclic sesquiterpenoids (413 and 414) were isolated from the culture medium of Amycolatopsis alba DSM 44262 [261]. Among the secondary metabolites of Isoptericola chiayiensis BCRC 16888, a new sesquiterpenoid isopterchiayione (415) was registered [262]. A new trichoacorenol sesquiterpene synthase from Amycolatopsis benzoatilytica DSM 43387 catalyzing the formation of a bicyclic sesquiterpenoid (416) was described [263]. Verrucosispora gifhornensis YM28-088 [264] and Verrucosispora sp. FIM06031 produced bicyclic sesquiterpenoid cyperusol C (417) and FW03104 (418) (CN101898936), respectively.

Terpene synthases from Streptosporangium roseum DSM 43021 and Kitasatosporia setae KM-6054 afforded tricyclic sesquiterpenoids epi-cubebol (419) [265] and new corvol ethers A (420) and B (421) [265,266], respectively. The terpene synthase from Saccharothrix espanaensis DSM 44229 [103] was incubated with FPP to yield a sesquiterpene (E)-β-caryophyllene (93).

413	414	415
416	417	418
419	420	421

2.2.2. Di- and Triterpenes and Their Derivatives

The TS from Micromonospora marina DSM 45555 was functionally characterized to produce micromonocyclol (422), a new diterpene alcohol with a rare 15-membered ring [267]. Mycobacterium tuberculosis H37Rvн synthesized unique bicyclic diterpenoids, which presumably block the formation of phagolysosomes in human macrophages. The Rv3377c and Rv3378c genes proved to be responsible for synthesis of tuberculosinol (5(6),13(14)-halimadiene-15-ol, 423), 13R- (424) and 13S-isotuberculosinol (5(6),14(15)-halimadiene-13-ol, 425), and nosyberkol (426) (previously identified as edaxadiene). The analogs of Rv3377c and Rv3378c were found in the virulent strains of M. tuberculosis CDC1551 and M. bovis subsp. bovis AF2122/97, but did not occur in non-pathogenic strains [268,269,270,271,272]. Later, the crystal structure of the Rv3377 diterpene synthase was described [273].

A bicyclic terpenoid terpentecin (427) was firstly separated from the fermentation broth of Kitasatosporia griseola MF730-N6 (syn. Streptomyces griseolosporeus MF730-N6) in 1985 [274]. A BGC responsible for the terpentecin biosynthesis includes seven ORFs (ORF8-ORF14). Expression of two cyclase genes ORF11 and ORF12 in S. lividans together with the GGDP synthase gene resulted in the formation of a new cyclic diterpene ent-clerod-3,13(16),14-triene (terpentetriene, 428) with a structure similar to 427 [275,276,277]. CYC2, which converted terpentedienyl phosphate (429) to 428, accepted labdane-type diterpene diphosphates (+)-CDP (430), syn-CDP (431), (−)-ent-CDP (432), as well as halimane-type diterpene diphosphate (TBPP, 433) and catalyzed the formation of corresponding derivatives (434–437) [278].

Heterologous expression of the biosynthetic terp1 operon from Salinispora arenicola CNS-205 in E. coli led to the generation of isopimara-8,15-dien-19-ol (438). It should be noted that this terpenoid was not observed in pure cultures of S. arenicola CNS-205. Apparently, the terp1 operon was expressed under certain conditions, for example, in the presence of other marine organisms [279]. The terpene synthase Sat1646 from Salinispora sp. PKU-MA00418 accepted CPP and syn-CPP and produced syn-isopimaradiene/pimaradiene analogues (180, 439–446). Compound 439 possess a unique and previously unreported 6-6-7 ring skeleton [150]. New hydroxylated derivatives of isopimaradiene, gifhornenolones A (447) and B (448), were isolated from the culture medium of Verrucosispora gifhornenensis YM28-088 [264]. Among secondary metabolites of Micromonospora haikouensis G039 [280] and Microbispora hainanensis CSR-4 [281], new diterpenoids isopimara-2-one-3-ol-8,15-diene (449) and 2α-hydroxy-8(14),15-pimaradien-17,18-dioic acid (450) were identified, respectively.

Actinomadura sp. SpB081030SC-15 [282] and Actinomadura sp. KC 191 [283] synthesized new JBIR-65 (451) and actinomadurol (452), rare bacterial C-19 norditerpenoids. A norditerpenoid k4610422 (453), originally discovered from a mesophilic rare actinomycete of the genus Streptosporangium, was isolated from the culture extract of a thermophilic actinomycete Actinomadura sp. AMW41E2 [284].

422	423	424	425
426	427	428	429
430 R=αH 431 R=βH	432	433	434
435	436	437
438	439	440	441
442	443	444	445
446	447	448	449
450	451	452		453

Diterpene synthases from Catenulispora acidiphila DSM 44928 and Saccharopolyspora spinosa NRRL 18395 produced new di- and tricyclic catenul-14-en-6-ol (454), isocatenula-2,14-diene (455), isocatenula-2(6),14-diene (456) [285], and spinodienes A (457), B (458), and 2,7,18-dolabellatriene (459) [286], respectively. All obtained compounds are characterized by unique carbon skeletons.

Terpene synthases isolated from Nocardia testacea NBRC 100365 and N. rhamnosiphila NBRC 108938 accepted GGPP, but not GPP, FPP, or GFPP as a substrate, which was converted by both enzymes in a tetracyclic diterpene phomopsene (460) [169]. Allokutzneria albata DSM 44149 encoded four diterpene synthases that catalyze the formation of mono-, tri-, and tetracyclic compounds: new spiroalbatene (461), bonnadiene (462) and allokutznerene (463), and known compounds: cembrene A (164), thunbergol (464), phomopsene (460), and spiroviolene (200) [287,288].

Hopanoid lipids (465–482) were found in the genus Frankia [289] with the highest level among all known organisms. Short stretches of DNA have been identified that are thought to contain squalene-hopene cyclase genes (shc) [290]. A new sesquarterpenoid identified as heptaprenylcycline B (483) was isolated from the cell walls of nonpathogenic mycobacteria [291,292].

454	455	456	457
458	459	460	461
462	463	464

465 R1	466 R1	467 R1				472 R1	473 R1		474 R1
468 R1						475 R1
R1			469 R2=H 470 R2=-COCH2CH3 471 R2=-COCH2C6H5			R1			476 R2=H 477 R2=-COCH2CH3 478 R2=-COCH2C6H5
479					480			481
482				483

2.2.3. Hybrid Metabolites (Meroterpenoids)

Verrucosispora sp. FIM06031 synthesized bicyclic sesquiterpenoid FW03105 (484) (CN101921721). Saccharomonospora sp. CNQ-490 produced saccharoquinoline (485), meroterpenoid with drimane-type sesquiterpene unit [293]. Two new halimane-type diterpenoids, micromonohalimanes A (486) and B (487), were derived from Micromonospora sp. WMMC-218, a symbiont of marine ascidians Symplegma brakenhielmi [294]. Further research of Rv3378c from Mycobacterium tuberculosis H37Rvн revealed that this enzyme catalyzed the formation of 1-tuberculosinyladenosine (488) and its two isomers, one of which was identified as N⁶-tuberculosinyladenosine (489). Compounds 488 and 489 are specific diterpene nucleosides of pathogen of Mycobacterium tuberculosis and can serve as chemical markers of infection [295,296,297]. Heterologous expression of gene pair Rv3377c-Rv3378c from M. tuberculosis H37Rvн in M. kansasii led to the production of 1-tuberculosinyladenosine (488) [298].

The ability of Nocardia brasiliensis IFM 0406 (now N. terpenica) to synthesize diterpene glycoside brasilicardin A (490) was first described in 1999 [299]. Brasilicardin A (490) displays a unique structure consisting of a diterpene skeleton with L-rhamnose, N-acetylglucosamine, amino acid, and 3-hydroxybenzoate components [300]. Later, three new terpenoids were derived from N. terpenica IFM0406 and identified as brasilicardins B–D (491–493) [301]. The heterologous expression of a biosynthetic cluster (bra0-12), responsible for the synthesis of 490, in Amycolatopsis japonicum (A. japonicum::bcaAB01) led to the formation of four brasilicardin congeners, namely BraC (492), BraD (493), BraC-agl (BraE, 494), and BraD-agl (BraF, 495) [302,303,304,305]. The use of the S. griseus::bcaAB01 (pRHAMO) transformant containing the biosynthetic cluster of brasilicardin A and a plasmid with a biosynthetic cassette for the generation of TDP-L-rhamnose resulted in increased yields of compounds 492 (1669 mg/L), 495 (926 mg/L), and a new metabolite (496) (15 mg/L). The target 490 was obtained through a five-step chemical modification of 494 [306].

Cloning and activation of the atolypene (ato) gene cluster from Amycolatopsis tolypomycina NRRL B-24205 in S. albus led to the characterization of two unprecedented tricyclic sesterterpenoids atolypenes A (497) and B (498) [307]. Terretonin N (499), a new highly oxygenated unique tetracyclic 6-hydroxymeroterpenoid, was derived from Nocardiopsis sp. LGO5 [308].

484	485	486	487
488		489
			490 R=OCH3
			491 R=H
492 R=OCH3 493 R=H		494 R=OCH3 495 R=H
496
		499
	497 R
	498 R

3. Discussion

The present review demonstrates that actinomycetes synthesize a wide variety of terpene derivatives ranging from monocyclic monoterpenes to polycyclic tri- and tetraterpenes and their various derivatives. Most actinomycete terpene derivatives are produced by Streptomyces, however, terpene biosynthesis by Allokutzneria, Amycolatopsis, Frankia, Kitasatosporia, Nocardia, Salinispora, Verrucosispora, etc., have been recently reported (Figure 3). The total number of identified terpenes and their derivatives exceeds 500. Among terpenes and terpenoids, sesqui- and diterpenoids predominate. The ability of streptomycetes to synthesize a wide range of hybrid metabolites (meroterpenoids), the total number of which exceeds 190, was shown. More than 350 actinomycete-derived terpenoids and meroterpenoids are novel compounds and frequently with unique carbon skeletons (Figure 4).

An extensive development of genome-sequencing technologies and bioinformatics tools have allowed the discovery of BCGs (including silent ones) in the genome of actinomycetes. That terpenoids and meroterpenoids are predominantly found among Streptomyces strains is presumably due to plenty of available genetic information about this group of actinomycetes. As of 26 June 2022, 1784 scaffold-level and 745 complete-level genome sequences of Streptomyces strains were available in the NCBI database. Recent genetic studies have shown that the biosynthetic potential of these actinomycetes is enormous. A genome-wide analysis of 22 Streptomyces species revealed more than 900 biosynthetic clusters; for most of these, the products are still unidentified [309]. In addition, Streptomyces are preferred hosts for the heterologous expression of terpene biosynthetic clusters from other microorganisms [48,50,310]. Since 2015, high biosynthetic potential of actinomycete genera such as Saccharopolyspora [311], Nocardiopsis [312], Rhodococcus [313,314], Salinispora [315], Verrucosispora [316], and Actinomadura [317] have been demonstrated. For instance, a genome-wide analysis of terpentecin- or brasilicardin-producing strains K. griseola MF730-N6 [318] and N. terpenica IFM0406 [319] revealed 15 and 47 BGCs yielding unidentified natural products, respectively. One of the main problems in terpene biosynthesis is that most biosynthetic clusters are silent; therefore, searching for methods of their activation is an urgent research direction. Currently, great success has been achieved in this field due to methods of heterologous expression and/or genome editing of the native producer [320]. Genomic data of the described actinomycete species demonstrated that 90% of the biosynthetic potential of these microorganisms is untapped yet and the possibility of discovering novel terpenoids with potential therapeutic effects remains [15,52,310,321]. Microbial collections can serve as a “springboard” for the discovery and patenting of new producers of bioactive terpene derivatives, as they include identified and well-characterized pure microbial cultures. For instance, the Regional Specialized Collection of Alkanotrophic Microorganisms (acronym IEGM, Perm, Russia; World Federation for Culture Collections # 285; USU 73559; http://www.iegmcol.ru/strains, accessed on 25 March 2022) contains more than 3000 strains of actinomycetes with a wide range of metabolic capabilities, which are promising for biocatalytic production of terpene derivatives [322,323,324,325,326] (RU0002529365).

Unlike the biosynthesis of well-studied secondary metabolites, such as polyketides and nonribosomal peptides, the prediction of terpene structures requires detailed understanding of the cyclization mechanisms and the structural characteristics of bacterial TSs [321,327]. In this regard, a separate research area is isolation of individual actinomycete terpene synthases, and description of their structural and mechanistic characteristics, as well as the study of terpene cyclization mechanisms. The crystal structures of linalool/nerolidol, 2-methylisoborneol, germacradienol/germacrene D, selina-4(15),7(11)-diene, epi-zizaene, pentalenene, cucumene, (E)-biformene synthases, and other TSs isolated from streptomycetes were characterized. In turn, genome mining of streptomycetes as producers of naphthoquinone-based meroterpenoids led to the discovery of unique prenyltransferase (PTase) and vanadium-dependent haloperoxidase enzymes (VHPO) [182,183]. For instance, the high-resolution crystal structures of two homologous members of the VHPO family associated with napiradiomycin biosynthesis, NapH1 and NapH3, were characterized [184]. It has been found that bacterial TSs, PTases, and VHPOs differ significantly from the plant or fungi ones as well as from each other. Moreover, they are capable of producing dozens of different compounds, which distinguishes them from most bacterial biosynthetic enzymes [46]. By the example of an epi-zizaene synthase, the successful application of site-directed mutagenesis of the enzyme to control the range of the compounds produced was proved [110,122] (WO2015120431).

Actinomycetes produce terpenoids with various biological and pharmacological activities such as antimicrobial, anticancer, antioxidant, antiviral, anti-inflammatory, immunosuppressive, etc. (Table 2). However, the bioactivity for most of the new actinomycete-derived terpenoids has not yet been determined but may be discovered in the future. For instance, napyridymycins A1 and A80915 A, B, C, D were originally known as antimicrobial agents, but after 2010, their high antiviral and cytotoxic activity have been determined. Among the biologically active actinomycete terpenoids, compounds with pronounced antimicrobial activity predominate (Figure 5A). They seem to inhibit the growth of extraneous microflora and render actinomycetes competitive in the microbial community. This statement is confirmed by the fact that some actinomycetes begin to produce terpenoids in the presence of other microorganisms. Thus, S. cinnabarinus PK209 and S. hygroscopicus HOK021 (NITE P-02560) synthesize the diterpene lobocompactol and the antibiotic platensimycin in the presence of the Gram-negative Alteromonas sp. KNS-16 [140] and the Gram-positive Tsukamurella pulmonis TP-B0596 (JP2019149945), respectively. The effectiveness of actinomycete terpenoids and meroterpenoids, namely pentalenolactone, albaflavenone, platensimycin, platencin, terpentecin, lavanducyanin, marinocyanins A–C, furaquinocin L, 3-dechloro-3-bromonapyradiomycin A1, napyradiomycin A1, and merochlorin A, as promising antibiotics has been proven. This is true for cyslabdan, which enhances the action (1000-fold) of the antibiotic imipenem against MRSA. In addition to high antibacterial activity, many meroterpenoids, such as napyradiomycins B1, B3, B4, A80915A, B, C, furaquinocins A and B, murayaquinone, marinocyanin A–C, and saccharoquinoline, exhibit a high cytotoxic activity against different cancer cell lines (Figure 5B).

The high biological activity of meroterpenoids is probably associated with the addition of an isoprene fragment to the pharmacophore polyketide part that increases the affinity for biological membranes. The unique biological and structural properties of meroterpenoids contribute to the search for methods of their total and semi-synthetic synthesis [328,329,330].

Actinomycete-derived terpenoids participate in specific interactions with macroorganisms (plants and animals), regulate the bacterial life cycle, perform protective functions, or serve as taxonomic markers. Bacterial terpenoids are often optical isomers of plant terpenoids and may represent two chemical communication channels that do not overlap even if the same habitat is occupied by prokaryotic and eukaryotic organisms producing terpenes [103]. Soil-smelling terpenoids geosmin and 2-methylisoborneol were shown to play the role of signaling molecules for springtails (Collembola), which spread Streptomyces spores in the soil [331]. According to other reports, these terpenoids are aposematic signals used to indicate the unpleasant taste qualities of toxin-producing microbes, preventing predation by eukaryotes [332]. Čihák et al. (2017) pointed out that during germination of S. coelicolor M145 spores, they synthesize albaflavenone, which may coordinate the development of the producer (quorum sensing) and/or play a role in the competitive repression of microflora (quorum suppression) in the natural environment [117]. In the liquid culture, S. coelicolor A3(2) does not produce aminobacteriohopanetriol or produces this compound in negligible amounts. However, the triterpene generation increased sharply during the formation of an aerial mycelium and sporulation, which may be associated with structural changes in the membrane and protection against water loss [176]. In addition, some TSs and terpene derivatives are so unique that they can become a taxonomic trait and be used to identify different groups of actinomycetes. For instance, the bioinformatics analysis of all sequenced Micromonospora isolates revealed TS genes, which differ significantly from other groups of characterized bacterial TSs and may be useful as markers of the genus, while Mycobacterium tuberculosis H37Rvн produced specific diterpene nucleosides, 1- and N⁶-tuberculosinyladenosines, promising for development as specific diagnostic markers of tuberculosis.

Despite the significant (more than 300) number of publications on terpene biosynthesis by actinomycetes, the conducted patent analysis revealed only 26 patents in this research area (Table S1). Terpenoids such as linalool, geosmin, caryolan-1-ol, and pseudopterosin intermediates as well as meroterpenoids, namely napyradiomycins A4, A80915, bixiamycins, and sulfonylbixiamycins, were obtained from native or genetically modified streptomycetes, their genetic constructs, or individual terpene synthases. The relatively small number of active patents may be due to the initial stage of research in this area. In addition, wild-type strains are not suitable for commercial purposes, as they produce low quantities of target products.

Table 2. Biologically active terpene derivatives derived from actinomycetes.

Compound	Previously Isolated from Other Sources	Strain/Enzyme		Patent	Biological Activity
Mono- and sesquiterpenes
1,8-Cineole (1)	Yes	Streptomyces clavuligerus ATCC 27064	[53,54,55]	WO2018142109	anti-inflammatory antioxidant	[333]
Linalool (2)	Yes	Streptomyces clavuligerus ATCC 27064	[53,54,55]	WO2020234307 WO2018142109	anticancer antimicrobial neuroprotective anxiolytic antidepressant anti-stress hepatoprotective	[334]
		Streptomyces sp. GWS-BW-H5	[53]
Nerolidol (3)	Yes	Streptomyces clavuligerus ATCC 27064	[53,54,55]	WO2018142109 WO2020234307	antimicrobial anti-biofilm antioxidant antiparasitic skin-penetration enhancer skin-repellent antinociceptive anti-inflammatory anticancer	[335]
α-Pinene (7) β-Pinene (8)	Yes	Streptomyces coelicolor A3(2)	[63]		antimicrobial	[336]
Limonene (9)	Yes	Streptomyces coelicolor A3(2)	[63]		antimicrobial antioxidant anti-inflammatory antidiabetic	[337]
γ-Terpinene (10) δ-Terpinene (11)	Yes	Streptomyces coelicolor A3(2)	[63]		antioxidant	[338]
(1R)-(+)-Camphor (12)	Yes	Streptomyces coelicolor A3(2)	[65]		insecticidal	[339]
(-)-epi-α-Bisabolol (18)	Yes	Streptomyces citricolor NBRC 13005	[67]		anti-inflammatory analgesic antibiotic anticancer	[340]
Germacrene B (26) Germacrene D (24)	Yes	TS from Streptomyces pristinaespiralis ATCC 25486	[82]		antileishmanial antiproliferative	[341]
		SAV76 from Streptomyces avermitilis	[83]
		SpS from Streptomyces xinghaiensis S187	[84]
		Streptomyces hygroscopicus NRRL 15879	[66]
Bicyclogermacrene (28)	Yes	SpS from Streptomyces xinghaiensis S187	[84]		antibacterial antifungal	[342]
Isopterchiayione (415)	No	Isoptericola chiayiensis BCRC 16888	[262]		anti-inflammatory (IC50 24.72 ± 1.25 µM)	[262]
Cyperusol C (417)	Yes	Verrucosispora gifhornensis YM28-088	[264]		antiviral (against hepatitis B virus, IC50 14.1 ± 1.1 µM)	[343]
epi-Cubenol (31)	Yes	Streptomyces sp. GWS-BW-H5	[53]		antifungal	[344]
		Transf. Streptomyces lividans TK21 gecA from Streptomyces griseus IFO13350	[87]
		Streptomyces albolongus YIM 101047	[73]
		Streptomyces griseus NBRC102592	[88]
		Streptomyces roseosporus NRRL 11379	[5]
		Streptomyces sp. SirexAA-E	[5]
		Streptomyces roseosporus NRRL15998	[237]
		Streptomyces flavogriseus ATCC33331	[237]
Kandenol A (36) Kandenol B (37) Kandenol C (38) Kandenol D (39) Kandenol E (40)	No	Streptomyces sp. HKI0595	[90]		antimicrobial (against Bacillus subtilis, Mycobacterium vaccae, MIC 12.5–50 µM)	[90]
(2R,4S,8αR)-8,8α,1,2,3,4-Hexahydro-2-hydroxy-4,8α-dimethyl-2(2H)-naphthalenone (52)	No	Streptomyces sp. XM17	[96]		antiviral (against influenza A virus, IC50 5–49 nM)	[96]
(1S,3S,4S,4αS,8αR)-4,8α-Dimethyloctahydronaphthalene-1,3,4α(3H)-triol (53)
(4S,4αS,8αS)-Octahydro-4α-hydroxy-4,8α-dimethyl-1(2H)-naphthalenone (54)
(1β,4β,4aβ,8aα)-4,8α-Dimethyloctahydronaphthalene-1,4a(2H)-diol (55)	No	Streptomyces albolongus YIM 101047	[73]		antifungal (against Candida parapsilosis, MIC 3.13 µg/mL)	[73]
(-)-δ-Cadinene (58)	Yes	SSCG_02150 from Streptomyces clavuligerus ATCC 27074	[97]		antimicrobial	[345]
T-Muurolol (59)	Yes	SSCG_03688 from Streptomyces clavuligerus ATCC 27074	[97]		antifungal	[346]
		Streptomyces sp. M491	[98]
15-Hydroxy-T-muurolol (61)	No	Streptomyces sp. M491	[98]		antitumor (IC50 6.7 µg/mL)	[98]
10-epi-δ-Eudesmol (86)	Yes	Streptomyces chartreusis NRRL 3882	[5]		repellent (against Aedes aegypti and ticks)	[102,347]
β-Eudesmol (72)	Yes	Streptomyces exfoliatus SMF19	[66]		potential antitumor potential antiangiogenic antimicrobial	[348,349]
		Streptomyces hygroscopicus NRRL 15879	[66]
Aromadendrene oxide-(2) (79)	Yes	Streptomyces hygroscopicus NRRL 15879	[66]		antibacterial antitumor	[350]
(-)-β-Cedrene (126) (+)-β-Cedrene (127)	Yes	Streptomyces hygroscopicus NRRL 15879	[66]	WO2015120431	antibacterial	[351]
		epi-isozizaene synthase from Streptomyces coelicolor A3(2)	[110,122]
β-Patchoulene (77)	Yes	Streptomyces hygroscopicus NRRL 15879	[66]		anti-inflammatory	[352]
α-Elemol (80)	Yes	Streptomyces parvulus B1682	[66]		insecticidal (against Ixodes scapularis, Amblyomma americanum)	[353]
		Streptomyces chartreusis NRRL 3882	[102]
Caryophyllene (93)	Yes	Streptomyces yanglinensis 3-10	[62]		anticancer antioxidant antimicrobial	[354,355]
		Saccharothrix espanaensis DSM 44229	[103]
Caryolan-1-ol (94)	Yes	Streptomyces griseus	[105]		antifungal (against Botrytis cinerea, IC50 0.026 µM/mL)	[107]
		Transf. Streptomyces lividans with gcoA from S. griseus
		Streptomyces globisporus TFH56	[106]
		Streptomyces griseus S4–7	[107]	WO2018062668
		Streptomyces albolongus YIM 101047	[73]
Albaflavenone (109)	No	Streptomyces coelicolor A3 (2)	[112]		antibacterial (against Bacillus subtilis, MIC 8–10 µg/mL)	[356]
		Transf. Streptomyces avermitilis SUKA16 with sav3032 and sav4925 from S. avermitilis	[119]
		Streptomyces cyaneogriseus subsp. noncyanogenus	[5]
		Streptomyces spectabilis NRRL-2792	[118]
		Streptomyces viridochromogenes DSM 40736	[116]
		Streptomyces griseoflavus Tu4000	[116]
		Streptomyces ghanaensis ATCC 14672	[116]
		Streptomyces albus ATCC 2396	[116]
		Streptomyces sp. CRB46	[115]
		Streptomyces coelicolor M145	[117]
		Streptomyces albidoflavus DSM 5415		WO1995007878
(Z)-α-Bisabolene (115) (Z)-γ-Bisabolene (117)	Yes	epi-isozizaene synthase Streptomyces coelicolor A3(2)	[110,122]	WO2015120431	antioxidant	[357]
Curcumene (116)	Yes	epi-isozizaene synthase Streptomyces coelicolor A3(2)	[110,122]		antifungal	[358]
Sesquiphellandrene (118)	Yes	epi-isozizaene synthase Streptomyces coelicolor A3(2)	[110,122]		antiproliferative	[359]
Strepsesquitriol (136)	No	Streptomyces sp. SCSIO 10355	[123]		anti-inflammatory	[123]
Pentalenolactone (132)	No	Streptomyces exfoliatus UC5319 Streptomyces avermitilis Streptomyces arenae TÜ469	[130]		antimicrobial antiviral	[125]
		Streptomyces albus JA 3453-10		DD261608
1-Deoxy-8α-hydroxypentalenic acid (150)	No	Streptomyces sp. NRRL S-4	[134]		antimicrobial (against Staphylococcus aureus, MIC 16 μg/mL; Escherichia coli, MIC 16–32 μg/mL)	[134]
1-Deoxy-9β-hydroxy-11-oxopentalenic acid (151)
Dihydro-β-agarofuran (78)	Yes	Streptomyces hygroscopicus NRRL 15879	[66]		insecticidal	[360]
Caryolan-1,9β-diol (96)	Yes	Streptomyces sp. AH25	[108]		anti-inflammatory (ED50 0.34 mg/ear)	[361]
		Streptomyces albolongus YIM 101047	[73]
Viridiflorol (91)	Yes	SAV_76 from Streptomyces avermitilis	[83]		anti-inflammatory antioxidant (against DPPH, IC50 74.7 µg/mL)	[362]
Di- and triterpenes and their derivatives
Lobocompactol (166)	No	Streptomyces cinnabarinus PK209	[140]		antifouling (against macroalga Ulva pertusa, EC50 0.18 µg/mL; diatom Navicula annexa; EC50 0.43 µg/mL)	[140]
Microeunicellol A (168)	No	Streptomyces albogriseolus SY67903	[142]		antitumor (against MCF-7, IC50 5.3 μM; MDA-MB-231, IC50 8.6 μM)	[142]
Terpentecin (427)	No	Kitasatosporia griseola MF730-N6	[202]		antibacterial (against Staphylococcus aureus, Bacillus subtilis, Corynebacterium bovis, Shigella dysenteriae, Aeromonas salmonicida, Vibrio anguillarum, MIC 0.05 µg/mL)	[274]
Isopimara-8(9),15-diene (180)	Yes	Streptomyces sp. PKU-TA00600	[150]		anti-inflammatory	[363]
		Sat1646 from Salinispora sp. PKU-MA00418
Isopimara-7(8),15-diene (445) Isopimara-8(14),15-diene (446) Syn-isopimara-7(8),15-diene (440) 8β-Isopimara-9(11),15-diene (441) 8β-Pimara-9(11),15-diene (442) Syn-stemod-13(17)-ene (443) Syn-pimara-7(8),15-diene (444)	No
2α-Hydroxy-8(14),15-pimaradien-17,18-dioic acid (450)	No	Microbispora hainanensis CSR-4	[281]		anti-Alzheimer neuroprotective (1 ng/mL) antitumor antioxidant	[281]
Gifhornenolone A (447)	No	Verrucosispora gifhornensis YM28-088	[264]		antiandrogenic (IC50 2.8 µg/mL)	[264]
Actinomadurol (452)	No	Actinomadura sp. KC 191	[283]		antibacterial (against Staphylococcus aureus, Kocuria rhizophila, Proteus hauseri, MIC 0.39–0.78 μg/mL)	[283]
k4610422 (453)	No	Actinomadura sp. AMW41E2	[284]		cytotoxic (against P388, IC50 30 μM)	[284]
Cyclooctatin (184)	No	Streptomyces melanosporofaciens MI614-43F2			anti-inflammatory	[364]
		Transf. E. coli with CotB3 or CotB4 from Streptomyces afghaniensis
		Streptomyces sp. KCB17JA11
3,7,18-Dolabellatriene (188)	Yes	Mutant W288G of CotB2 from Streptomyces melanosporofaciens MI614-43F2	[158]		antimicrobial (against methicillin-resistant Staphylococcus aureus, MIC 16.0 µg/mL)	[365]
2,7,18-Dolabellatriene (459)		Saccharopolyspora spinosa NRRL 18395	[286]
Thunbergol (464)	Yes	Allokutzneria albata DSM 44149	[287]		antimicrobial	[366]
Meroterpenoids
Furaquinocin A (226) Furaquinocin B (227)	No	Streptomyces sp. KO-3988 Streptomyces sp. CLl90	[185]	WO2006081537	antitumor (against HeLa S3, IC50 1.6–3.1 μg/mL)	[185]
Furaquinocin C (228) Furaquinocin D (226) Furaquinocin E (234) Furaquinocin G (235) Furaquinocin H (231)	No	Streptomyces sp. KO-3988			cytotoxic (against B16, IC50 0.08–6.87 μg/mL; HeLa S3, IC50 0.22–5.05 μg/mL)
Furaquinocin L (238)	No	Streptomyces sp. Je 1-369	[191]		antibacterial (against Staphylococcus aureus, MIC 2.0 μg/mL)	[191]
Murayaquinone (240)	No	Streptomyces sp. TBRC7642	[188]		antitubercular (MIC 3.13 μg/mL)	[188]
					cytotoxic (against MCF-7 IC50 6.0 μM; NCI–H187, IC500.85 μM; Vero, IC502.05 μM)
Merochlorin A (241)	No	Streptomyces sp. CNH-189	[192]		antibacterial (against MRSA, MIC 2.0–4.0 μg/mL; Clostridium difficile 0.3–0.15 μg/mL)	[192]
Merochlorin I (249)	No	Streptomyces sp. CNH-189	[194]		antibacterial (against Bacillus subtilis, MIC 1.0 μg/mL; Kocuria rhizophila, MIC 2.0 μg/mL; Staphylococcus aureus, MIC 2.0 μg/mL)	[194]
Merochlorin E (245) Merochlorin F (246)	No	Streptomyces sp. CNH-189	[193]		antibacterial (against Bacillus subtilis, MIC 1.0 µg/mL, Kocuria rhizophila MIC 2.0 μg/mL, Staphylococcus aureus MIC 1.0–2.0 μg/mL)	[193]
Flaviogeranin D (256) Flaviogeranin C2 (258)	No	Streptomyces sp. B9173	[196]		antibacterial (against Mycobacterium smegmatis, MIC 5.2 μg/mL)	[196]
					cytotoxic (against A549, IC50 0.6–0.9 μM; Hela, IC50 0.4–1.1 μM)
Flaviogeranin A (252)		Streptomyces sp. RAC226	[195]		neuroprotective (EC50 8.6 nM)	[195]
Naphterpin (259)	No	Streptomyces sp. CL190 Streptomyces sp. strain CLl90	[197]	WO2006081537	antioxidant (suppressed lipid peroxidation in rat homogenate system, IC50 5.3 μg/mL)	[197]
Naphterpin B (260) Naphterpin C (261)	No	Streptomyces sp. CL190	[199]		antioxidant (suppressed lipid peroxidation in rat homogenate system, IC50 6.0–6.5 μg/mL)	[199]
Napyradiomycin CNQ-525.1 (226)	No	Streptomyces sp. CNQ-525	[208]		antibacterial (against MRSA, MIC 1.95 μg/mL; Enterococcus faecium (VREF) MIC 1.9–3.9 μg/mL)	[208]
Napyradiomycin CNQ-525.2 (281)
Napyradiomycin CNQ-525.3 (282)					cytotoxic (against HCT, IC50 1.0–2.4 μg/mL)
Napyradiomycin CNQ-525.4 (283)
Napyradiomycin D1 (287)	No	Streptomyces sp. CA-271078	[203]		antibacterial (against MRSA, MIC 12.0–24.0 μg/mL; Mycobacterium tuberculosis, MIC 12.0–48.0 μg/mL)	[203]
					cytotoxic (HepG2, IC50 14.9 μM)
3-Dechloro-3-bromonapyradiomycin A1 (266)	No	Streptomyces sp. SCSIO 10428 Streptomyces kebangsaanensis WS-68302 Streptomyces sp. CA-271078	[201,204]	CN105399721	antibacterial (against Staphylococcus aureus, MIC 0.5–1.0 μg/mL; MRSA, MIC 4.0–8.0 μg/mL; Bacillus subtilis, MIC 1.0–2.0 μg/mL; Bacillus thuringiensis, MIC 0.5–2.0 μg/mL) cytotoxic (against HCT-116, IC50 2.0–3.0 μM)	[201,204,209]
Napyradiomycin B1 (273)
Naphthomevalin (289)
Napyradiomycin A1 (264)	No	Streptomyces sp. CA-271078	[201]		antibacterial (against MRSA, MIC 0.5–1.0 μg/mL)	[201]
		Streptomyces sp. YP127	[200]		antiangiogenic	[200]
		Streptomyces kebangsaanensis WS-68302		CN105399721	antibacterial (against Staphylococcus aureus, MIC 0.078 µg/mL) antiviral (against Pseudorabies virus, IC50 2.2 μg/mL)
Napyradiomycin B2 (275)	No	Streptomyces sp. CNQ-329 Streptomyces sp. CNH-070	[206]		cytotoxic (against HCT-116, IC50 3.18 μg/mL) antibacterial (against MRSA, MIC 3.0–6.0 μg/mL)	[206]
		Streptomyces sp. CA-271078	[203]
Napyradiomycin B3 (274)	No	Streptomyces sp. CNQ-329 Streptomyces sp. CNH-070	[206]		cytotoxic (against HCT-116, IC50 0.2 μg/mL) antibacterial (against MRSA, MIC 2.0 μg/mL; against Staphylococcus aureus, MIC 0.5 μg/mL; Bacillus subtilis, MIC 0.2 μg/mL; Bacillus thuringiensis, MIC 0.5 μg/mL)	[203,206]
		Streptomyces sp. SCSIO 10428	[203]
Napyradiomycin B4 (284)		Streptomyces strains CNQ-329 and CNH-070	[206]		cytotoxic (against HCT-116, IC50 1.41 μg/mL)	[206]
NPM 1 (288)		Streptomyces strains CNQ-329 and CNH-070	[206]		cytotoxic (against HCT-116, IC50 4.2–4.8 μg/mL)	[206]
Napyradiomycin CNQ525.538 (271)	No	Streptomyces sp. CNQ-525	[209]		cytotoxic (against HCT-116, IC50 6.0 μg/mL)	[209]
A80915A (277) A80915B (278) A80915D (279) A80915G (291)	No	Streptomyces aculeolatus A80915	-	EP0376609	antibacterial (against Staphylococcus aureus, MIC 0.03–4.0 μg/mL; S. epidermidis, MIC 0.15–2.0 μg/mL; Streptococcus pyogenes, MIC 0.03–2.0 μg/mL; S. pneumonia, MIC 0.125–2.0 μg/mL; Enterococcus faecium, MIC 1.0–4.0 μg/mL; E. faecalis, MIC 1.0 μg/mL; Haemophilus influenzae, MIC 0.008 μg/mL; Clostridium difficile, MIC 2.0–4.0 μg/mL; C. perfringers, MIC 2.0–4.0 μg/mL; C. septicum, MIC 1.0–2.0 μg/mL; Eubacterium aerofaciens, MIC 0.5–2.0 μg/mL; Peptococcus asaccharolyticus, MIC 0.5–4.0 μg/mL; P. prevotii, MIC 1.0–2.0 μg/mL; P. intermediatus, MIC 1.0–2.0 μg/mL; Propionibacterium acnes, MIC 0.5–1.0 μg/mL; Bacteroides fragilis, MIC 2.0–4.0; B. melaninogenicus, MIC 0.5–2.0 μg/mL; B. corrodens, MIC 2.0–4.0 μg/mL; Fusobacterium symbiosum, MIC 0.5–4.0 μg/mL)	-
A80915A (277) A80915B (278) A80915D (279)	No	Streptomyces sp. CNQ-525	[209]		cytotoxic (against HCT-116, IC50 1.0–3.0 μg/mL)	[209]
7-Demethyl SF2415A3 (272) 7-Demethyl A80915B (285)	No	Streptomyces antimycoticus NT17	[202]		antibacterial (against Staphylococcus aureus, MIC 2.0–3.7 nM/mL; Bacillus subtilis, MIC 1.0–3.7 nM/mL)	[202]
Napyradiomycin A4 (267)	No	Streptomyces kebangsaanensis WS-68302		CN114805278	antiviral (against Pseudorabies virus (PRV), IC50 2.056 μM)
16Z-19-Hydroxynapyradiomycin A1 (265)	No	Streptomyces sp. YP127	[205]		anti-inflammatory antioxidant	[205]
(R)-3-Chloro-6-hydroxy-8-methoxy-alpha-lapachone (286)	No	Streptomyces sp. YP127 Streptomyces antimycoticus NT17	[202,205]		anti-inflammatory	[205]
Marfuraquinocin A (292) Marfuraquinocin C (294) Marfuraquinocin D (295)	No	Streptomyces niveus SCSIO 3406	[210]		cytotoxic (against NCI-H460, IC50 3.7; 4.4; 8.8 μM) antibacterial (against Staphylococcus aureus ATCC 29213, methicillin-resistant Staphylococcus epidermidis, MIC 8.0 μg/mL)	[210]
FW03105 (484)	No	Verrucosispora sp. FIM06031		CN101921721	antitumor (against HepG2, IC50 16.99 µM; EC109, IC50 25.33 µM; HeLA, IC50 34.64 µM)
Saccharoquinoline (492)	No	Saccharomonospora sp. CNQ-490	[293]		cytotoxic (against HCT-116, IC50 1.0 μM)	[293]
Teleocidin B (314)	No	Streptomyces mediocidicus	[211]		tumor promoter	[211]
		Streptomyces sp. 680560	[367]		nematicidal	[367]
		Streptomyces blastmyceticus	[214]
Lavanducyanin (304)	No	Streptomyces sp. CNS-284 and CNY-960 Streptomyces sp. CLl90	[216]	WO2006081537	cytotoxic (against HCT-116, IC50 2.41 μM)	[216]
					antimicrobial (against Staphylococcus aureus, MIC 2.92 μM; Candida albicans, MIC 5.96 μM)
Marinocyanin A (298) Marinocyanin B (299) Marinocyanin C (300)	No	Streptomyces sp. CNS-284 и CNY-960	[216]	-	cytotoxic (against HCT-116, IC50 0.029–0.049 μM)	[216]
					antimicrobial (against Staphylococcus aureus, MIC 2.37 μM; Candida albicans, MIC 0.95–3.90 μM)
Farneside A (306)	No	Streptomyces sp. CNT-372	[217]		antimalarial (against Plasmodium falciparum)	[217]
Xiamycin A (310)		Streptomyces sp. SCSIO 02999	[220]	CN102757908 CN102732534	antiviral anti-HIV cytotoxic	[220]
		Streptomyces sp. GT2002/1503	[221]		antiviral (against SARS-CoV-2)	[368]
		Streptomyces sp. HKI0595	[226]		antiviral (against HSV-1)	[329]
Xiamycin methyl ester (311)	No	Streptomyces sp. SCSIO 02999	[220]	CN102757908	antitumor (IC50 10.13 μM)
					antiviral (against SARS-CoV-2)	[368]
Dixiamycin A (328) Dixiamycin B (330)	No	Streptomyces sp. GT2002/1503	[221]		antibacterial (against E. coli, S. aureus, MIC 8–16 µg/mL; B. thuringiensis, MIC 4–8 µg/mL)	[221]
		Streptomyces xinghaiensis NRRL B-24674T	[228]
		Streptomyces sp. SCSIO 02999		CN102757908
Dixiamycin 6a/6b (333/334)	No	Transf. S. albus with xia from Streptomyces sp. SCSIO 02999	[230]	WO2014029498	antibacterial (against MRSA, MIC 0.2 µg/mL)	[230]
Dixiamycin 8 (337)					antibacterial (against S. aureus, MRSA, MIC 1.56 µg/mL)
Dixiamycin 7a/7b (335/336)	No	Streptomyces olivaceus OUCLQ19-3	[229]		antibacterial (S. aureus, E. faecalis, E. faecium, M. luteus, P. aeruginosa, MIC 6.25–12.5 µg/mL)	[229]
Dixiamycin 12a/12b (331/332)					antibacterial (S. aureus, MIC 0.78–3.12 µg/mL; E. faecalis, E. faecium, M. luteus, MIC 3.12–6.25 µg/mL; P. aeruginosa, MIC 1.56 µg/mL)
Xiamycin B (313) Indosespene (318)	No	Streptomyces sp. HKI0595 Streptomyces sp. SCSIO 02999	[226]	CN102732534	antimicrobial (against MRSA; vancomycin-resistant Enterococcus faecalis)	[226]
Sespenine (319)					antiviral (against SARS-CoV-2)	[368]
Xiamycin D (324)	No	Streptomyces sp. HK18	[225]		antiviral (against PEDV)	[225]
Xiamycin C (323)					antiviral (against SARS-CoV-2)	[368]
Oridamycin A (326)	No	Streptomyces sp. KS84	[227]		antifungal (against Saprolegnia parasitica, MIC 3.0 µg/mL)	[227]
Sulfonylbixiamycin A (338)	No	Transf. S. albus with xiamycin BGC from Streptomyces sp.	[231]	WO2014029498	antibacterial (against Bacillus subtilis, MIC 6.25 µg/mL; Staphylococcus aureus, MIC 3.12 µg/mL; MRSA, MIC 6.25 µg/mL)	[231]
Cyslabdan A (341)	No	Streptomyces cyslabdanicus K04-0144	[233]		enhance (1000-fold) the antibiotic imipenem action (against MRSA)	[369]
Oxaloterpin A (347)	No	Streptomyces sp. KO-3988	[151]		antibacterial (against Bacillus subtilis ATCC 43223, IC50 1.9 µM/mL; Staphylococcus aureus ATCC29213; EC50 3.7)	[151]
		Streptomyces griseus CB00830	[235]
		Streptomyces sp. SN194	[152]
Chloroxaloterpin A (352) Chloroxaloterpin B (353)	No	Streptomyces sp. SN194	[152]		antifungal (against Botrytis cinerea, EC50 4.40–4.96 µg/mL)	[152]
Fusicomycin A (384) Fusicomycin (385) Fusicomycin B (386)	No	Streptomyces violascens YIM 100212	[164]		cytotoxicity (against BGC-823 H460, HCT116, HeLa, SMMC7721 8.9, IC50 from 3.5 ± 0.7 to 14.1 ± 0.8 µM)	[164]
Streptooctatin A (387) Streptooctatin B (388)	No	Streptomyces sp. KCB17JA11	[243]		autophagic (against HeLa)	[243]
Actinoranone (389)		Streptomyces sp. CNQ-027	[244]		cytotoxic (against HCT-116, LD50 2.0 μg/mL)	[244]
Brasilicardin A (490)	No	Nocardia brasiliensis IFM 0406 (now N. terpenica)	[299]		immunosuppressive	[300]
					antiproliferative (against LN229, IC50 0.13 μM)	[306]
Platensimycin (390) Platencin (391)		Streptomyces platensis MA7327 Streptomyces platensis MA7339 Streptomyces platensis MA7237	[245,246]	US20090081673	antibacterial (against S. aureus (MRSA), Enterococcus faecalis, Enterococcus faecium, MIC 0.1–1.0 μg/mL)	[245,246]
Atolypene A (497) Atolypene B (498)	No	Transf. Streptomyces albus with ato gene cluster from Amycolatopsis tolypomycina NRRL B-24205	[307]		cytotoxic (against HL-60, Jurkat, HEK293, HeLa, A549, IC50 12.0–36.7 μM)	[307]
Terretonin N (499)	No	Nocardiopsis sp. LGO5	[308]		antibacterial (against Staphylococcus warneri)	[308]
Soyasaponin I (407)	Yes	Streptomyces sp. YIM 56130	[94]		anti-inflammatory antimutagenic anticarcinogenic antimicrobial	[256]
Longestin (408)	No	Streptomyces argenteolus A-2	[257]		antiamnesic (IC50 0.065 µM)	[370]

Table 2. Biologically active terpene derivatives derived from actinomycetes.

Compound	Previously Isolated from Other Sources	Strain/Enzyme		Patent	Biological Activity
Mono- and sesquiterpenes
1,8-Cineole (1)	Yes	Streptomyces clavuligerus ATCC 27064	[53,54,55]	WO2018142109	anti-inflammatory antioxidant	[333]
Linalool (2)	Yes	Streptomyces clavuligerus ATCC 27064	[53,54,55]	WO2020234307 WO2018142109	anticancer antimicrobial neuroprotective anxiolytic antidepressant anti-stress hepatoprotective	[334]
		Streptomyces sp. GWS-BW-H5	[53]
Nerolidol (3)	Yes	Streptomyces clavuligerus ATCC 27064	[53,54,55]	WO2018142109 WO2020234307	antimicrobial anti-biofilm antioxidant antiparasitic skin-penetration enhancer skin-repellent antinociceptive anti-inflammatory anticancer	[335]
α-Pinene (7) β-Pinene (8)	Yes	Streptomyces coelicolor A3(2)	[63]		antimicrobial	[336]
Limonene (9)	Yes	Streptomyces coelicolor A3(2)	[63]		antimicrobial antioxidant anti-inflammatory antidiabetic	[337]
γ-Terpinene (10) δ-Terpinene (11)	Yes	Streptomyces coelicolor A3(2)	[63]		antioxidant	[338]
(1R)-(+)-Camphor (12)	Yes	Streptomyces coelicolor A3(2)	[65]		insecticidal	[339]
(-)-epi-α-Bisabolol (18)	Yes	Streptomyces citricolor NBRC 13005	[67]		anti-inflammatory analgesic antibiotic anticancer	[340]
Germacrene B (26) Germacrene D (24)	Yes	TS from Streptomyces pristinaespiralis ATCC 25486	[82]		antileishmanial antiproliferative	[341]
		SAV76 from Streptomyces avermitilis	[83]
		SpS from Streptomyces xinghaiensis S187	[84]
		Streptomyces hygroscopicus NRRL 15879	[66]
Bicyclogermacrene (28)	Yes	SpS from Streptomyces xinghaiensis S187	[84]		antibacterial antifungal	[342]
Isopterchiayione (415)	No	Isoptericola chiayiensis BCRC 16888	[262]		anti-inflammatory (IC50 24.72 ± 1.25 µM)	[262]
Cyperusol C (417)	Yes	Verrucosispora gifhornensis YM28-088	[264]		antiviral (against hepatitis B virus, IC50 14.1 ± 1.1 µM)	[343]
epi-Cubenol (31)	Yes	Streptomyces sp. GWS-BW-H5	[53]		antifungal	[344]
		Transf. Streptomyces lividans TK21 gecA from Streptomyces griseus IFO13350	[87]
		Streptomyces albolongus YIM 101047	[73]
		Streptomyces griseus NBRC102592	[88]
		Streptomyces roseosporus NRRL 11379	[5]
		Streptomyces sp. SirexAA-E	[5]
		Streptomyces roseosporus NRRL15998	[237]
		Streptomyces flavogriseus ATCC33331	[237]
Kandenol A (36) Kandenol B (37) Kandenol C (38) Kandenol D (39) Kandenol E (40)	No	Streptomyces sp. HKI0595	[90]		antimicrobial (against Bacillus subtilis, Mycobacterium vaccae, MIC 12.5–50 µM)	[90]
(2R,4S,8αR)-8,8α,1,2,3,4-Hexahydro-2-hydroxy-4,8α-dimethyl-2(2H)-naphthalenone (52)	No	Streptomyces sp. XM17	[96]		antiviral (against influenza A virus, IC50 5–49 nM)	[96]
(1S,3S,4S,4αS,8αR)-4,8α-Dimethyloctahydronaphthalene-1,3,4α(3H)-triol (53)
(4S,4αS,8αS)-Octahydro-4α-hydroxy-4,8α-dimethyl-1(2H)-naphthalenone (54)
(1β,4β,4aβ,8aα)-4,8α-Dimethyloctahydronaphthalene-1,4a(2H)-diol (55)	No	Streptomyces albolongus YIM 101047	[73]		antifungal (against Candida parapsilosis, MIC 3.13 µg/mL)	[73]
(-)-δ-Cadinene (58)	Yes	SSCG_02150 from Streptomyces clavuligerus ATCC 27074	[97]		antimicrobial	[345]
T-Muurolol (59)	Yes	SSCG_03688 from Streptomyces clavuligerus ATCC 27074	[97]		antifungal	[346]
		Streptomyces sp. M491	[98]
15-Hydroxy-T-muurolol (61)	No	Streptomyces sp. M491	[98]		antitumor (IC50 6.7 µg/mL)	[98]
10-epi-δ-Eudesmol (86)	Yes	Streptomyces chartreusis NRRL 3882	[5]		repellent (against Aedes aegypti and ticks)	[102,347]
β-Eudesmol (72)	Yes	Streptomyces exfoliatus SMF19	[66]		potential antitumor potential antiangiogenic antimicrobial	[348,349]
		Streptomyces hygroscopicus NRRL 15879	[66]
Aromadendrene oxide-(2) (79)	Yes	Streptomyces hygroscopicus NRRL 15879	[66]		antibacterial antitumor	[350]
(-)-β-Cedrene (126) (+)-β-Cedrene (127)	Yes	Streptomyces hygroscopicus NRRL 15879	[66]	WO2015120431	antibacterial	[351]
		epi-isozizaene synthase from Streptomyces coelicolor A3(2)	[110,122]
β-Patchoulene (77)	Yes	Streptomyces hygroscopicus NRRL 15879	[66]		anti-inflammatory	[352]
α-Elemol (80)	Yes	Streptomyces parvulus B1682	[66]		insecticidal (against Ixodes scapularis, Amblyomma americanum)	[353]
		Streptomyces chartreusis NRRL 3882	[102]
Caryophyllene (93)	Yes	Streptomyces yanglinensis 3-10	[62]		anticancer antioxidant antimicrobial	[354,355]
		Saccharothrix espanaensis DSM 44229	[103]
Caryolan-1-ol (94)	Yes	Streptomyces griseus	[105]		antifungal (against Botrytis cinerea, IC50 0.026 µM/mL)	[107]
		Transf. Streptomyces lividans with gcoA from S. griseus
		Streptomyces globisporus TFH56	[106]
		Streptomyces griseus S4–7	[107]	WO2018062668
		Streptomyces albolongus YIM 101047	[73]
Albaflavenone (109)	No	Streptomyces coelicolor A3 (2)	[112]		antibacterial (against Bacillus subtilis, MIC 8–10 µg/mL)	[356]
		Transf. Streptomyces avermitilis SUKA16 with sav3032 and sav4925 from S. avermitilis	[119]
		Streptomyces cyaneogriseus subsp. noncyanogenus	[5]
		Streptomyces spectabilis NRRL-2792	[118]
		Streptomyces viridochromogenes DSM 40736	[116]
		Streptomyces griseoflavus Tu4000	[116]
		Streptomyces ghanaensis ATCC 14672	[116]
		Streptomyces albus ATCC 2396	[116]
		Streptomyces sp. CRB46	[115]
		Streptomyces coelicolor M145	[117]
		Streptomyces albidoflavus DSM 5415		WO1995007878
(Z)-α-Bisabolene (115) (Z)-γ-Bisabolene (117)	Yes	epi-isozizaene synthase Streptomyces coelicolor A3(2)	[110,122]	WO2015120431	antioxidant	[357]
Curcumene (116)	Yes	epi-isozizaene synthase Streptomyces coelicolor A3(2)	[110,122]		antifungal	[358]
Sesquiphellandrene (118)	Yes	epi-isozizaene synthase Streptomyces coelicolor A3(2)	[110,122]		antiproliferative	[359]
Strepsesquitriol (136)	No	Streptomyces sp. SCSIO 10355	[123]		anti-inflammatory	[123]
Pentalenolactone (132)	No	Streptomyces exfoliatus UC5319 Streptomyces avermitilis Streptomyces arenae TÜ469	[130]		antimicrobial antiviral	[125]
		Streptomyces albus JA 3453-10		DD261608
1-Deoxy-8α-hydroxypentalenic acid (150)	No	Streptomyces sp. NRRL S-4	[134]		antimicrobial (against Staphylococcus aureus, MIC 16 μg/mL; Escherichia coli, MIC 16–32 μg/mL)	[134]
1-Deoxy-9β-hydroxy-11-oxopentalenic acid (151)
Dihydro-β-agarofuran (78)	Yes	Streptomyces hygroscopicus NRRL 15879	[66]		insecticidal	[360]
Caryolan-1,9β-diol (96)	Yes	Streptomyces sp. AH25	[108]		anti-inflammatory (ED50 0.34 mg/ear)	[361]
		Streptomyces albolongus YIM 101047	[73]
Viridiflorol (91)	Yes	SAV_76 from Streptomyces avermitilis	[83]		anti-inflammatory antioxidant (against DPPH, IC50 74.7 µg/mL)	[362]
Di- and triterpenes and their derivatives
Lobocompactol (166)	No	Streptomyces cinnabarinus PK209	[140]		antifouling (against macroalga Ulva pertusa, EC50 0.18 µg/mL; diatom Navicula annexa; EC50 0.43 µg/mL)	[140]
Microeunicellol A (168)	No	Streptomyces albogriseolus SY67903	[142]		antitumor (against MCF-7, IC50 5.3 μM; MDA-MB-231, IC50 8.6 μM)	[142]
Terpentecin (427)	No	Kitasatosporia griseola MF730-N6	[202]		antibacterial (against Staphylococcus aureus, Bacillus subtilis, Corynebacterium bovis, Shigella dysenteriae, Aeromonas salmonicida, Vibrio anguillarum, MIC 0.05 µg/mL)	[274]
Isopimara-8(9),15-diene (180)	Yes	Streptomyces sp. PKU-TA00600	[150]		anti-inflammatory	[363]
		Sat1646 from Salinispora sp. PKU-MA00418
Isopimara-7(8),15-diene (445) Isopimara-8(14),15-diene (446) Syn-isopimara-7(8),15-diene (440) 8β-Isopimara-9(11),15-diene (441) 8β-Pimara-9(11),15-diene (442) Syn-stemod-13(17)-ene (443) Syn-pimara-7(8),15-diene (444)	No
2α-Hydroxy-8(14),15-pimaradien-17,18-dioic acid (450)	No	Microbispora hainanensis CSR-4	[281]		anti-Alzheimer neuroprotective (1 ng/mL) antitumor antioxidant	[281]
Gifhornenolone A (447)	No	Verrucosispora gifhornensis YM28-088	[264]		antiandrogenic (IC50 2.8 µg/mL)	[264]
Actinomadurol (452)	No	Actinomadura sp. KC 191	[283]		antibacterial (against Staphylococcus aureus, Kocuria rhizophila, Proteus hauseri, MIC 0.39–0.78 μg/mL)	[283]
k4610422 (453)	No	Actinomadura sp. AMW41E2	[284]		cytotoxic (against P388, IC50 30 μM)	[284]
Cyclooctatin (184)	No	Streptomyces melanosporofaciens MI614-43F2			anti-inflammatory	[364]
		Transf. E. coli with CotB3 or CotB4 from Streptomyces afghaniensis
		Streptomyces sp. KCB17JA11
3,7,18-Dolabellatriene (188)	Yes	Mutant W288G of CotB2 from Streptomyces melanosporofaciens MI614-43F2	[158]		antimicrobial (against methicillin-resistant Staphylococcus aureus, MIC 16.0 µg/mL)	[365]
2,7,18-Dolabellatriene (459)		Saccharopolyspora spinosa NRRL 18395	[286]
Thunbergol (464)	Yes	Allokutzneria albata DSM 44149	[287]		antimicrobial	[366]
Meroterpenoids
Furaquinocin A (226) Furaquinocin B (227)	No	Streptomyces sp. KO-3988 Streptomyces sp. CLl90	[185]	WO2006081537	antitumor (against HeLa S3, IC50 1.6–3.1 μg/mL)	[185]
Furaquinocin C (228) Furaquinocin D (226) Furaquinocin E (234) Furaquinocin G (235) Furaquinocin H (231)	No	Streptomyces sp. KO-3988			cytotoxic (against B16, IC50 0.08–6.87 μg/mL; HeLa S3, IC50 0.22–5.05 μg/mL)
Furaquinocin L (238)	No	Streptomyces sp. Je 1-369	[191]		antibacterial (against Staphylococcus aureus, MIC 2.0 μg/mL)	[191]
Murayaquinone (240)	No	Streptomyces sp. TBRC7642	[188]		antitubercular (MIC 3.13 μg/mL)	[188]
					cytotoxic (against MCF-7 IC50 6.0 μM; NCI–H187, IC500.85 μM; Vero, IC502.05 μM)
Merochlorin A (241)	No	Streptomyces sp. CNH-189	[192]		antibacterial (against MRSA, MIC 2.0–4.0 μg/mL; Clostridium difficile 0.3–0.15 μg/mL)	[192]
Merochlorin I (249)	No	Streptomyces sp. CNH-189	[194]		antibacterial (against Bacillus subtilis, MIC 1.0 μg/mL; Kocuria rhizophila, MIC 2.0 μg/mL; Staphylococcus aureus, MIC 2.0 μg/mL)	[194]
Merochlorin E (245) Merochlorin F (246)	No	Streptomyces sp. CNH-189	[193]		antibacterial (against Bacillus subtilis, MIC 1.0 µg/mL, Kocuria rhizophila MIC 2.0 μg/mL, Staphylococcus aureus MIC 1.0–2.0 μg/mL)	[193]
Flaviogeranin D (256) Flaviogeranin C2 (258)	No	Streptomyces sp. B9173	[196]		antibacterial (against Mycobacterium smegmatis, MIC 5.2 μg/mL)	[196]
					cytotoxic (against A549, IC50 0.6–0.9 μM; Hela, IC50 0.4–1.1 μM)
Flaviogeranin A (252)		Streptomyces sp. RAC226	[195]		neuroprotective (EC50 8.6 nM)	[195]
Naphterpin (259)	No	Streptomyces sp. CL190 Streptomyces sp. strain CLl90	[197]	WO2006081537	antioxidant (suppressed lipid peroxidation in rat homogenate system, IC50 5.3 μg/mL)	[197]
Naphterpin B (260) Naphterpin C (261)	No	Streptomyces sp. CL190	[199]		antioxidant (suppressed lipid peroxidation in rat homogenate system, IC50 6.0–6.5 μg/mL)	[199]
Napyradiomycin CNQ-525.1 (226)	No	Streptomyces sp. CNQ-525	[208]		antibacterial (against MRSA, MIC 1.95 μg/mL; Enterococcus faecium (VREF) MIC 1.9–3.9 μg/mL)	[208]
Napyradiomycin CNQ-525.2 (281)
Napyradiomycin CNQ-525.3 (282)					cytotoxic (against HCT, IC50 1.0–2.4 μg/mL)
Napyradiomycin CNQ-525.4 (283)
Napyradiomycin D1 (287)	No	Streptomyces sp. CA-271078	[203]		antibacterial (against MRSA, MIC 12.0–24.0 μg/mL; Mycobacterium tuberculosis, MIC 12.0–48.0 μg/mL)	[203]
					cytotoxic (HepG2, IC50 14.9 μM)
3-Dechloro-3-bromonapyradiomycin A1 (266)	No	Streptomyces sp. SCSIO 10428 Streptomyces kebangsaanensis WS-68302 Streptomyces sp. CA-271078	[201,204]	CN105399721	antibacterial (against Staphylococcus aureus, MIC 0.5–1.0 μg/mL; MRSA, MIC 4.0–8.0 μg/mL; Bacillus subtilis, MIC 1.0–2.0 μg/mL; Bacillus thuringiensis, MIC 0.5–2.0 μg/mL) cytotoxic (against HCT-116, IC50 2.0–3.0 μM)	[201,204,209]
Napyradiomycin B1 (273)
Naphthomevalin (289)
Napyradiomycin A1 (264)	No	Streptomyces sp. CA-271078	[201]		antibacterial (against MRSA, MIC 0.5–1.0 μg/mL)	[201]
		Streptomyces sp. YP127	[200]		antiangiogenic	[200]
		Streptomyces kebangsaanensis WS-68302		CN105399721	antibacterial (against Staphylococcus aureus, MIC 0.078 µg/mL) antiviral (against Pseudorabies virus, IC50 2.2 μg/mL)
Napyradiomycin B2 (275)	No	Streptomyces sp. CNQ-329 Streptomyces sp. CNH-070	[206]		cytotoxic (against HCT-116, IC50 3.18 μg/mL) antibacterial (against MRSA, MIC 3.0–6.0 μg/mL)	[206]
		Streptomyces sp. CA-271078	[203]
Napyradiomycin B3 (274)	No	Streptomyces sp. CNQ-329 Streptomyces sp. CNH-070	[206]		cytotoxic (against HCT-116, IC50 0.2 μg/mL) antibacterial (against MRSA, MIC 2.0 μg/mL; against Staphylococcus aureus, MIC 0.5 μg/mL; Bacillus subtilis, MIC 0.2 μg/mL; Bacillus thuringiensis, MIC 0.5 μg/mL)	[203,206]
		Streptomyces sp. SCSIO 10428	[203]
Napyradiomycin B4 (284)		Streptomyces strains CNQ-329 and CNH-070	[206]		cytotoxic (against HCT-116, IC50 1.41 μg/mL)	[206]
NPM 1 (288)		Streptomyces strains CNQ-329 and CNH-070	[206]		cytotoxic (against HCT-116, IC50 4.2–4.8 μg/mL)	[206]
Napyradiomycin CNQ525.538 (271)	No	Streptomyces sp. CNQ-525	[209]		cytotoxic (against HCT-116, IC50 6.0 μg/mL)	[209]
A80915A (277) A80915B (278) A80915D (279) A80915G (291)	No	Streptomyces aculeolatus A80915	-	EP0376609	antibacterial (against Staphylococcus aureus, MIC 0.03–4.0 μg/mL; S. epidermidis, MIC 0.15–2.0 μg/mL; Streptococcus pyogenes, MIC 0.03–2.0 μg/mL; S. pneumonia, MIC 0.125–2.0 μg/mL; Enterococcus faecium, MIC 1.0–4.0 μg/mL; E. faecalis, MIC 1.0 μg/mL; Haemophilus influenzae, MIC 0.008 μg/mL; Clostridium difficile, MIC 2.0–4.0 μg/mL; C. perfringers, MIC 2.0–4.0 μg/mL; C. septicum, MIC 1.0–2.0 μg/mL; Eubacterium aerofaciens, MIC 0.5–2.0 μg/mL; Peptococcus asaccharolyticus, MIC 0.5–4.0 μg/mL; P. prevotii, MIC 1.0–2.0 μg/mL; P. intermediatus, MIC 1.0–2.0 μg/mL; Propionibacterium acnes, MIC 0.5–1.0 μg/mL; Bacteroides fragilis, MIC 2.0–4.0; B. melaninogenicus, MIC 0.5–2.0 μg/mL; B. corrodens, MIC 2.0–4.0 μg/mL; Fusobacterium symbiosum, MIC 0.5–4.0 μg/mL)	-
A80915A (277) A80915B (278) A80915D (279)	No	Streptomyces sp. CNQ-525	[209]		cytotoxic (against HCT-116, IC50 1.0–3.0 μg/mL)	[209]
7-Demethyl SF2415A3 (272) 7-Demethyl A80915B (285)	No	Streptomyces antimycoticus NT17	[202]		antibacterial (against Staphylococcus aureus, MIC 2.0–3.7 nM/mL; Bacillus subtilis, MIC 1.0–3.7 nM/mL)	[202]
Napyradiomycin A4 (267)	No	Streptomyces kebangsaanensis WS-68302		CN114805278	antiviral (against Pseudorabies virus (PRV), IC50 2.056 μM)
16Z-19-Hydroxynapyradiomycin A1 (265)	No	Streptomyces sp. YP127	[205]		anti-inflammatory antioxidant	[205]
(R)-3-Chloro-6-hydroxy-8-methoxy-alpha-lapachone (286)	No	Streptomyces sp. YP127 Streptomyces antimycoticus NT17	[202,205]		anti-inflammatory	[205]
Marfuraquinocin A (292) Marfuraquinocin C (294) Marfuraquinocin D (295)	No	Streptomyces niveus SCSIO 3406	[210]		cytotoxic (against NCI-H460, IC50 3.7; 4.4; 8.8 μM) antibacterial (against Staphylococcus aureus ATCC 29213, methicillin-resistant Staphylococcus epidermidis, MIC 8.0 μg/mL)	[210]
FW03105 (484)	No	Verrucosispora sp. FIM06031		CN101921721	antitumor (against HepG2, IC50 16.99 µM; EC109, IC50 25.33 µM; HeLA, IC50 34.64 µM)
Saccharoquinoline (492)	No	Saccharomonospora sp. CNQ-490	[293]		cytotoxic (against HCT-116, IC50 1.0 μM)	[293]
Teleocidin B (314)	No	Streptomyces mediocidicus	[211]		tumor promoter	[211]
		Streptomyces sp. 680560	[367]		nematicidal	[367]
		Streptomyces blastmyceticus	[214]
Lavanducyanin (304)	No	Streptomyces sp. CNS-284 and CNY-960 Streptomyces sp. CLl90	[216]	WO2006081537	cytotoxic (against HCT-116, IC50 2.41 μM)	[216]
					antimicrobial (against Staphylococcus aureus, MIC 2.92 μM; Candida albicans, MIC 5.96 μM)
Marinocyanin A (298) Marinocyanin B (299) Marinocyanin C (300)	No	Streptomyces sp. CNS-284 и CNY-960	[216]	-	cytotoxic (against HCT-116, IC50 0.029–0.049 μM)	[216]
					antimicrobial (against Staphylococcus aureus, MIC 2.37 μM; Candida albicans, MIC 0.95–3.90 μM)
Farneside A (306)	No	Streptomyces sp. CNT-372	[217]		antimalarial (against Plasmodium falciparum)	[217]
Xiamycin A (310)		Streptomyces sp. SCSIO 02999	[220]	CN102757908 CN102732534	antiviral anti-HIV cytotoxic	[220]
		Streptomyces sp. GT2002/1503	[221]		antiviral (against SARS-CoV-2)	[368]
		Streptomyces sp. HKI0595	[226]		antiviral (against HSV-1)	[329]
Xiamycin methyl ester (311)	No	Streptomyces sp. SCSIO 02999	[220]	CN102757908	antitumor (IC50 10.13 μM)
					antiviral (against SARS-CoV-2)	[368]
Dixiamycin A (328) Dixiamycin B (330)	No	Streptomyces sp. GT2002/1503	[221]		antibacterial (against E. coli, S. aureus, MIC 8–16 µg/mL; B. thuringiensis, MIC 4–8 µg/mL)	[221]
		Streptomyces xinghaiensis NRRL B-24674T	[228]
		Streptomyces sp. SCSIO 02999		CN102757908
Dixiamycin 6a/6b (333/334)	No	Transf. S. albus with xia from Streptomyces sp. SCSIO 02999	[230]	WO2014029498	antibacterial (against MRSA, MIC 0.2 µg/mL)	[230]
Dixiamycin 8 (337)					antibacterial (against S. aureus, MRSA, MIC 1.56 µg/mL)
Dixiamycin 7a/7b (335/336)	No	Streptomyces olivaceus OUCLQ19-3	[229]		antibacterial (S. aureus, E. faecalis, E. faecium, M. luteus, P. aeruginosa, MIC 6.25–12.5 µg/mL)	[229]
Dixiamycin 12a/12b (331/332)					antibacterial (S. aureus, MIC 0.78–3.12 µg/mL; E. faecalis, E. faecium, M. luteus, MIC 3.12–6.25 µg/mL; P. aeruginosa, MIC 1.56 µg/mL)
Xiamycin B (313) Indosespene (318)	No	Streptomyces sp. HKI0595 Streptomyces sp. SCSIO 02999	[226]	CN102732534	antimicrobial (against MRSA; vancomycin-resistant Enterococcus faecalis)	[226]
Sespenine (319)					antiviral (against SARS-CoV-2)	[368]
Xiamycin D (324)	No	Streptomyces sp. HK18	[225]		antiviral (against PEDV)	[225]
Xiamycin C (323)					antiviral (against SARS-CoV-2)	[368]
Oridamycin A (326)	No	Streptomyces sp. KS84	[227]		antifungal (against Saprolegnia parasitica, MIC 3.0 µg/mL)	[227]
Sulfonylbixiamycin A (338)	No	Transf. S. albus with xiamycin BGC from Streptomyces sp.	[231]	WO2014029498	antibacterial (against Bacillus subtilis, MIC 6.25 µg/mL; Staphylococcus aureus, MIC 3.12 µg/mL; MRSA, MIC 6.25 µg/mL)	[231]
Cyslabdan A (341)	No	Streptomyces cyslabdanicus K04-0144	[233]		enhance (1000-fold) the antibiotic imipenem action (against MRSA)	[369]
Oxaloterpin A (347)	No	Streptomyces sp. KO-3988	[151]		antibacterial (against Bacillus subtilis ATCC 43223, IC50 1.9 µM/mL; Staphylococcus aureus ATCC29213; EC50 3.7)	[151]
		Streptomyces griseus CB00830	[235]
		Streptomyces sp. SN194	[152]
Chloroxaloterpin A (352) Chloroxaloterpin B (353)	No	Streptomyces sp. SN194	[152]		antifungal (against Botrytis cinerea, EC50 4.40–4.96 µg/mL)	[152]
Fusicomycin A (384) Fusicomycin (385) Fusicomycin B (386)	No	Streptomyces violascens YIM 100212	[164]		cytotoxicity (against BGC-823 H460, HCT116, HeLa, SMMC7721 8.9, IC50 from 3.5 ± 0.7 to 14.1 ± 0.8 µM)	[164]
Streptooctatin A (387) Streptooctatin B (388)	No	Streptomyces sp. KCB17JA11	[243]		autophagic (against HeLa)	[243]
Actinoranone (389)		Streptomyces sp. CNQ-027	[244]		cytotoxic (against HCT-116, LD50 2.0 μg/mL)	[244]
Brasilicardin A (490)	No	Nocardia brasiliensis IFM 0406 (now N. terpenica)	[299]		immunosuppressive	[300]
					antiproliferative (against LN229, IC50 0.13 μM)	[306]
Platensimycin (390) Platencin (391)		Streptomyces platensis MA7327 Streptomyces platensis MA7339 Streptomyces platensis MA7237	[245,246]	US20090081673	antibacterial (against S. aureus (MRSA), Enterococcus faecalis, Enterococcus faecium, MIC 0.1–1.0 μg/mL)	[245,246]
Atolypene A (497) Atolypene B (498)	No	Transf. Streptomyces albus with ato gene cluster from Amycolatopsis tolypomycina NRRL B-24205	[307]		cytotoxic (against HL-60, Jurkat, HEK293, HeLa, A549, IC50 12.0–36.7 μM)	[307]
Terretonin N (499)	No	Nocardiopsis sp. LGO5	[308]		antibacterial (against Staphylococcus warneri)	[308]
Soyasaponin I (407)	Yes	Streptomyces sp. YIM 56130	[94]		anti-inflammatory antimutagenic anticarcinogenic antimicrobial	[256]
Longestin (408)	No	Streptomyces argenteolus A-2	[257]		antiamnesic (IC50 0.065 µM)	[370]

4. Conclusions

Thus, the synthesis of terpenes and terpenoids is an important pathway in the secondary metabolism of actinomycetes. The compounds produced may be promising therapeutic agents for the treatment of viral, inflammatory, cancerous, and other diseases in the future. Terpenoids and meroterpenoids synthesized by actinomycetes and possessing high antibacterial activity against drug-resistant pathogenic microorganisms may be useful for the development of new antibiotics. Further study of actinomycetes, accumulation of genetic information about this group of microorganisms, and employment of modern and development of novel tools of synthetic biology and genetic engineering will open prospects for creation of ideal “cell factories” using actinomycetes.