Search Results (27)

Marine-derived rare actinomycetes are a chemically prolific yet underexploited source of structurally diverse secondary metabolites. In this review, rare actinomycetes are operationally defined as marine-derived non-Streptomyces actinomycetes that remain comparatively underexplored yet possess demonstrated or predicted capacity for specialized-metabolite biosynthesis. Genome sequencing has revealed that their biosynthetic potential greatly exceeds the range of metabolites recovered under standard cultivation conditions. However, many reported compounds remain only loosely associated with the gene clusters that encode them. This review provides a biosynthesis-centered perspective on marine-derived rare actinomycetes, focusing on secondary metabolites for which biosynthetic gene clusters (BGCs) or pathways have been proposed, experimentally assessed, or functionally validated. It focuses on compounds reported after 2017, along with earlier metabolites whose biosynthetic origins were resolved only later. Representative examples are organized by genus and structural class and weighed according to the level of evidence linking each metabolite to its BGC, ranging from bioinformatic prediction and metabolomic correlation to validation by gene inactivation, heterologous expression, and enzymatic characterization. The surveyed metabolites include polyketides, nonribosomal peptides, polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) hybrids, siderophores, angucyclines, anthracyclines, macrolides, diketopiperazine derivatives, and other unusual scaffolds. Collectively, these findings indicate how integrating genome mining, metabolomics, and molecular networking with targeted biosynthetic experiments can accelerate marine natural product discovery and unravel novel enzymatic functions and biosynthetic mechanisms in rare actinomycetes. Full article

Nenestatins (NENs) belong to benzo[b]fluorene-containing atypical angucyclines, a structurally diverse class of microbial natural products. Bioinformatic analysis of the NEN biosynthetic gene cluster (nes BGC) from the deep-sea sediment-derived Micromonospora echinospora SCSIO 04089 implicated Nes5 as an α/β hydrolase. The targeted inactivation of the nes5 gene led to the accumulation of five new analogs, NENs E–I (1–5), together with the known monomer homo-dehydrorabelomycin E (6). Their structures were elucidated by comprehensive spectroscopic analysis and electronic circular dichroism calculations. Notably, both NEN A and NEN B were absent in the Δnes5 mutant, indicating that Nes5 is essential for their biosynthesis; however, the exact function of Nes5 requires further exploration. Full article

Angucyclines/angucyclinones, a class of polyketides with diverse chemical structures, display various bioactivities including antibacterial or antifungal, anticancer, anti-neuroinflammatory, and anti-α-glucosidase activities. Marine and terrestrial microorganisms have made significant contributions to the discovery of bioactive angucyclines/angucyclinones. This review covers 283 bioactive angucyclines/angucyclinones discovered from 1965 to 2023, and the emphasis is on the biological origins, chemical structures, and biological activities of these interesting natural products. Full article

Heterologous expression has emerged as an effective strategy in activating Streptomyces cryptic gene clusters or improving yield. Eight compounds were successfully obtained by heterologous expression of the type II PKS gene cluster spi derived from marine Streptomyces sp. HDN155000 in the chassis host Streptomyces albus J1074. The structures with absolute configurations were elucidated using extensive MS and NMR spectroscopic methods, as well as theoretical NMR calculations and electronic circular dichroism (ECD) calculations. Interestingly, compound WS009 Z (2) contains a rare thiomethyl group, angumycinone T (4) has a novel oxo-bridge formed between C12a and C4, and angumycinone X (3) showed cytotoxicity toward K562 and NCI-H446/EP cell lines. Full article

Marine symbiotic and epiphyte microorganisms are sources of bioactive or structurally novel natural products. Metabolic blockade-based genome mining has been proven to be an effective strategy to accelerate the discovery of natural products from both terrestrial and marine microorganisms. Here, the metabolic blockade-based genome mining strategy was applied to the discovery of other metabolites in a sea anemone-associated Streptomyces sp. S1502. We constructed a mutant Streptomyces sp. S1502/Δstp1 that switched to producing the atypical angucyclines WS-5995 A–E, among which WS-5995 E is a new compound. A biosynthetic gene cluster (wsm) of the angucyclines was identified through gene knock-out and heterologous expression studies. The biosynthetic pathways of WS-5995 A–E were proposed, the roles of some tailoring and regulatory genes were investigated, and the biological activities of WS-5995 A–E were evaluated. WS-5995 A has significant anti-Eimeria tenell activity with an IC₅₀ value of 2.21 μM. The production of antibacterial streptopyrroles and anticoccidial WS-5995 A–E may play a protective role in the mutual relationship between Streptomyces sp. S1502 and its host. Full article

Recently, we re-isolated the glycosylated angucycline antibiotics P-1894B (1) and grincamycin (1′) from the marine-derived Streptomyces lusitanus SCSIO LR32 as potent antitumor agents and identified their biosynthesis gene cluster gcn. Both P-1894B (1) and grincamycin (1′) possess a trisaccharide and a disaccharide moiety comprised of five deoxysugars. In this work, three genes encoding glycosyltransferases (GcnG1, GcnG2, and GcnG3) responsible for the assembly of deoxysugars into angucycline aglycone were identified from the biosynthesis gene cluster gcn. Gene inactivations of gcnG1, gcnG2, gcnG3, and gcnG1G2 by lambda-RED-mediated gene replacements led to the construction of four mutants, in which the glycosyltransferase genes were disrupted, respectively. The metabolites from the mutants were purified and identified, including two new analogues designated as grincamycin U (3a) and V (3′). The sequential glycosylation steps in the biosynthesis of P-1894B (1) and grincamycin (1′) catalyzed by GcnG3, GcnG1, and GcnG2 were elucidated. Full article

The one strain many compounds (OSMAC) strategy is an effective method for activating silent gene clusters by cultivating microorganisms under various conditions. The whole genome sequence of the marine-derived strain Streptomyces globisporus SCSIO LCY30 revealed that it contains 30 biosynthetic gene clusters (BGCs). By using the OSMAC strategy, three types of secondary metabolites were activated and identified, including three angucyclines, mayamycin A (1), mayamycin B (2), and rabolemycin (3); two streptophenazines (streptophenazin O (4) and M (5)); and a macrolide dimeric dinactin (6), respectively. The biosynthetic pathways of the secondary metabolites in these three families were proposed based on the gene function prediction and structural information. The bioactivity assays showed that angucycline compounds 1–3 exhibited potent antitumor activities against 11 human cancer cell lines and antibacterial activities against a series of Gram-positive bacteria. Mayamycin (1) selectively exhibited potent cytotoxicity activity against triple-negative breast cancer (TNBC) cell lines such as MDA-MB-231, MDA-MB-468, and Bt-549, with IC₅₀ values of 0.60–2.22 μM. Full article

Six angucyclines including three unreported compounds (1–3) were isolated from Streptomyces sp. XS-16 by overexpressing the native global regulator of SCrp (cyclic AMP receptor). The structures were characterized based on nuclear magnetic resonance (NMR) and spectrometry analysis and assisted by electronic circular dichroism (ECD) calculations. All compounds were tested for their antitumor and antimicrobial activities, and compound 1 showed different inhibitory activities against various tumor cell lines with IC₅₀ values ranging from 0.32 to 5.33 μM. Full article

Chemical investigation of the ethyl acetate extract from the culture broth of the marine-derived actinobacterium Streptomyces ardesiacus 156VN-095 led to the isolation of three hitherto undescribed angucycline glycosides, including urdamycins W and X (1 and 2) and grincamycin U (9), as well as their seven known congeners. The structures of the new compounds were elucidated by means of spectroscopic methods (HRESIMS, 1D and 2 D NMR) and comparison of their experimental data with literature values. Compounds 1–3 and 9 were evaluated for their anti-Gram-positive bacterial effect and cytotoxicity against six cancer cell lines. Compound 1 displayed significant cytotoxicity against all the tested cell lines with GI₅₀ values of 0.019–0.104 µM. Collectively, these findings highlight the potential of angucycline glycosides as leading structures for the development of new anti-cancer drugs. Full article

Moromycin B (Mor B), saquayamycin B₁ (Saq B₁), saquayamycin B (Saq B), and landomycin N (Lan N), four angucyclines produced by the marine-derived actinomycete Streptomyces sp., are a class of polyketone compounds containing benzanthracene. Here, the structure–activity relationship of these four compounds was analyzed in human colorectal cancer (CRC) cells. Saq B₁, which showed the strongest cytotoxicity with an IC₅₀ of 0.18–0.84 µM for CRC cells in MTT assays, was employed to test underlying mechanisms of action in SW480 and SW620 cells (two invasive CRC cell lines). Our results showed that Saq B₁ inhibited CRC cell proliferation in a dose- and time-dependent manner. Notably, lower cytotoxicity was measured in normal human hepatocyte cells (QSG-7701). Furthermore, we observed proapoptosis, antimigration, and anti-invasion activities of Saq B₁ in CRC cells. At the same time, the protein and mRNA expression of important markers related to the epithelial–mesenchymal transition (EMT) and apoptosis changed, including N-cadherin, E-cadherin, and Bcl-2, in Saq B₁-treated CRC cells. Surprisingly, the PI3K/AKT signaling pathway was shown to be involved in Saq B₁-induced apoptosis, and in inhibiting invasion and migration. Computer docking models also suggested that Saq B₁ might bind to PI3Kα. Collectively, these results indicate that Saq B₁ effectively inhibited growth and decreased the motor ability of CRC cells by regulating the PI3K/AKT signaling pathway, which provides more possibilities for the development of drugs in the treatment of CRC. Full article

We previously identified the aur1 biosynthetic gene cluster (BGC) in Streptomyceslavendulae subsp. lavendulae CCM 3239 (formerly Streptomycesaureofaciens CCM 3239), which is responsible for the production of the unusual angucycline-like antibiotic auricin. Auricin is produced in a narrow interval of the growth phase after entering the stationary phase, after which it is degraded due to its instability at the high pH values reached after the production phase. The complex regulation of auricin BGC is responsible for this specific production by several regulators, including the key activator Aur1P, which belongs to the family of atypical response regulators. The aur1P gene forms an operon with the downstream aur1O gene, which encodes an unknown protein without any conserved domain. Homologous aur1O genes have been found in several BGCs, which are mainly responsible for the production of angucycline antibiotics. Deletion of the aur1O gene led to a dramatic reduction in auricin production. Transcription from the previously characterized Aur1P-dependent biosynthetic aur1Ap promoter was similarly reduced in the S. lavendulaeaur1O mutant strain. The aur1O-specific coactivation of the aur1Ap promoter was demonstrated in a heterologous system using a luciferase reporter gene. In addition, the interaction between Aur1O and Aur1P has been demonstrated by a bacterial two-hybrid system. These results suggest that Aur1O is a specific coactivator of this key auricin-specific positive regulator Aur1P. Bioinformatics analysis of Aur1O and its homologues in other BGCs revealed that they represent a new family of transcriptional coactivators involved in the regulation of secondary metabolite biosynthesis. However, they are divided into two distinct sequence-specific subclasses, each of which is likely to interact with a different family of positive regulators. Full article

Strain NJES-13^T is the type strain and currently the only species of the newly established actinobacteria genera Aptenodytes in the family Dermatophilaceae isolated from the gut microbiota of the Antarctic emperor penguin. This strain demonstrated excellent bioflocculation activity with bacteria-derived exopolysaccharides (EPSs). Moreover, it produced bioactive angucycline/angucyclinone derivatives (ADs) and contained one type III polyketide synthase (T3PKS), thus demonstrating great potential to produce novel bioactive compounds. However, the low productivity of the potential new AD metabolite was the main obstacle for its chemical structure elucidation. In this study, to increase the concentration of targeted metabolites, the influence of cellular morphology on AD metabolism in strain NJES-13^T was determined using glass bead-enhanced fermentation. Based on the cellular ultra-structural observation driven by bacterial EPSs, and quantitative analysis of the targeted metabolites, the successful increasing of the productivity of three AD metabolites was achieved. Afterward, a new frigocyclinone analogue was isolated and then identified as 2-hydroxy-frigocyclinone, as well as two other known ADs named 2-hydroxy-tetrangomycin (2-HT) and gephyromycin (GPM). Three AD metabolites were found to demonstrate different bioactivities. Both C-2 hydroxyl substitutes, 2-hydroxy-tetrangomycin and 2-hydroxy-frigocyclinone, exhibited variable inhibitory activities against Staphylococcus aureus, Bacillus subtilis and Candida albicans. Moreover, the newly identified 2-hydroxy-frigocyclinone also showed significant cytotoxicity against three tested human-derived cancerous cell lines (HL-60, Bel-7402 and A549), with all obtained IC₅₀ values less than 10 µM. Based on the genetic analysis after genomic mining, the plausible biogenetic pathway of the three bioactive ADs in strain NJES-13^T was also proposed. Full article

Coculture is a productive technique to trigger microbes’ biosynthetic capacity by mimicking the natural habitats’ features principally by competition for food and space and interspecies cross-talks. Mixed cultivation of two Red Sea-derived actinobacteria, Actinokineospora spheciospongiae strain EG49 and Rhodococcus sp. UR59, resulted in the induction of several non-traced metabolites in their axenic cultures, which were detected using LC–HRMS metabolomics analysis. Antimalarial guided isolation of the cocultured fermentation led to the isolation of the angucyclines actinosporins E (1), H (2), G (3), tetragulol (5) and the anthraquinone capillasterquinone B (6), which were not reported under axenic conditions. Interestingly, actinosporins were previously induced when the axenic culture of the Actinokineospora spheciospongiae strain EG49 was treated with signalling molecule N-acetyl-d-glucosamine (GluNAc); this finding confirmed the effectiveness of coculture in the discovery of microbial metabolites yet to be discovered in the axenic fermentation with the potential that could be comparable to adding chemical signalling molecules in the fermentation flask. The isolated angucycline and anthraquinone compounds exhibited in vitro antimalarial activity and good biding affinity against lysyl-tRNA synthetase (PfKRS1), highlighting their potential developability as new antimalarial structural motif. Full article

Antibiotic producers have mainly been isolated from soil, which often has led to the rediscovery of known compounds. In this study, we identified the freshwater snail Physa acuta as an unexplored source for new antibiotic producers. The bacterial diversity associated with the snail was characterized by a metagenomic approach using cultivation-independent high-throughput sequencing. Although Actinobacteria represented only 2% of the bacterial community, the focus was laid on the isolation of the genus Streptomyces due to its potential to produce antibiotics. Three Streptomyces strains (7NS1, 7NS2 and 7NS3) were isolated from P. acuta, and the antimicrobial activity of the crude extracts were tested against a selection of Gram-positive and Gram-negative bacteria and fungi. 7NS3 showed the strongest activity against Gram-positive bacteria and, thus, was selected for genome sequencing and a phylogenomic analysis. 7NS3 represents a novel Streptomyces species, which was deposited as Streptomyces sp. DSM 110735 at the Leibniz Institute-German Collection of Microorganisms and Cell Cultures (DSMZ). Bioassay-guided high-performance liquid chromatography (HPLC) and high-resolution electrospray ionization-mass spectrometry (HR-ESI-MS) analyses of crude extract fractions resulted in the detection of four compounds, one of which matched the compound characteristics of emycin A, an angucycline-like aromatic polyketide. Genome mining studies based on the whole-genome sequence of 7NS3 resulted in the identification of a gene cluster potentially coding for emycin A biosynthesis. Our study demonstrates that freshwater snails like P. acuta can represent promising reservoirs for the isolation of new antibiotic-producing actinobacterial species. Full article

The Philippine archipelago is geographically positioned in the tropics with rich areas of marine biodiversity. Its marine sediments harbor actinomycetes that exhibit antibacterial activity. Screening of actinomycetes isolated from marine sediments collected near the coast of Islas de Gigantes, Iloilo showed one isolate that exhibited high activity against the multidrug-resistant Staphylococcus aureus (MRSA) strain carrying the Staphylococcal Cassette Chromosome mec (SCCmec) type 1 gene, a biomarker for drug resistance. The isolate was identified as Streptomyces sp. strain DSD011 based on its 16s rRNA and protein-coding genes (atpD, recA, rpoB, and trpB) sequences, and was found to be a new species of salt-tolerant marine Streptomyces. Further, the strain harbors both non-ribosomal peptide synthetase (NRPS) and type II polyketide synthase (PKS) in its genome. The targeted chromatographic isolation and chemical investigations by Liquid Chromatography Mass Spectrometry-Time of Flight (LCMS-TOF), tandem mass spectrometry (MS/MS), and Global Natural Product Social molecular networking (GNPS) of the antibiotics produced by the strain afforded the two polycyclic aromatic polyketide angucycline glycosides, fridamycin A (1) and fridamycin D (2), which are products of type II PKS biosynthesis. Compounds 1 and 2 displayed antibacterial activity against MRSA with minimum inhibitory concentration (MIC) of 500 μg/mL and 62.5 μg/mL, respectively. These results suggest that the underexplored marine sediments near the coast of Islas de Gigantes, Iloilo offer access to undiscovered Streptomyces species that are invaluable sources of antibiotic leads. Full article