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24 October 2024

Unraveling the Biosynthetic Logic Behind the Production of Ramoplanin and Related Lipodepsipeptide Antibiotics

,
,
and
1
Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy
2
Department of Genetics and Biotechnology, Ivan Franko National University of Lviv, 79005 Lviv, Ukraine
*
Author to whom correspondence should be addressed.
Fermentation2024, 10(11), 544;https://doi.org/10.3390/fermentation10110544
This article belongs to the Section Microbial Metabolism, Physiology & Genetics
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Abstract

This review focuses on the genetic and biotechnological aspects of the biosynthesis of ramoplanin (Rmp), enduracidin (End), and other related lipodepsipeptide antibiotics, herein named collectively ramoplanin and ramoplanin-related lipodepsipeptide (RRLDPs). These compounds exhibit a promising antimicrobial activity against Gram-positive bacterial pathogens, showing no cross-resistance with vancomycin. Rmp is in clinical development for human treatment and End has been used as animal growth promoter for decades. Other RRLDPs as ramoplanose and janiemycin had been poorly investigated in the past, whereas new molecules as chersinamycin have been recently discovered, attracting a renewed interest in this class of antibiotics. Nowadays, sequence and annotation of the biosynthetic gene clusters (BGCs) of Rmp, End, and several other RRLDPs are available, and researchers are focused on understanding the biosynthetic logic behind the production of these compounds. Interestingly, producers of Rmp and chersinamycin belong to the so-called “non-common” actinomycetes from the family Micromonosporaceae, whereas End is produced by different members of the genus Streptomyces. To the best of our knowledge, no reviews summarize and systematize the current information on the biosynthesis of RRLDPs. Therefore, in this review, we aim to fill this gap. We first describe and compare the BGCs for known RRLDPs, giving an insight on how they were discovered and developed. Next, we review the biosynthetic pathways of these antibiotics, as well as the regulation of their biosynthesis. Then, we focus on the production processes of RRLDPs, demonstrating how cultivation and nutritional factors influence their production. Finally, we provide a short outline of future directions in studying RRLDPs.

1. Introduction

In the past century, a multitude of polypeptide antibiotics of bacterial origin has been isolated and investigated [1,2]. These can generally be divided into two superclasses based on their principal biosynthetic mechanisms: ribosomally synthesized and post-translationally modified peptides (RiPPs) [3], and non-ribosomally synthesized peptides (NRPs) (i.e., those produced involving non-ribosomal peptide synthetases [4]). Producers of the former and latter compounds have been discovered across various Gram-positive and Gram-negative bacterial lineages, although the members of the phylum Actinomycetota (traditionally named actinomycetes) represent the largest source of bacterial polypeptide antibiotics. Apart from actinomycetes, RiPPs have been predominantly found in Gram-positive bacteria from the phylum Bacillota, including Bacillus spp. (e.g., subtilin [5]), Lactococcus spp. (e.g., nisin [6]), Staphylococcus spp. (e.g., epidermin [7]), Streptococcus spp. (e.g., salivaricin [8]), Enterococcus spp. (e.g., cytolysin [9]), Carnobacterium spp. (carnocin [10]), or in Gram-negative myxobacteria (e.g., myxarylin in Pyxidicoccus fallax [11]). Producers of non-ribosomally synthesized peptide antibiotics have been identified within a much broader variety of bacterial phyla, including Bacillota (e.g., gramicidin and polymyxin from Bacillus brevis and Paenibacillus polymyxa, respectively [12,13]), Pseudomonadota (e.g., teixobactin from Eleftheria terrae and ajudazols from Chondromyces crocatus [14,15]), or Cyanobacteriota (e.g., anabaenopeptins from Planktothrix spp. [16]).
Among RiPPs and non-ribosomal peptide antibiotics, numerous compounds target different steps of peptidoglycan (PG) biosynthesis [17]. PG biosynthesis, intensively discussed elsewhere (e.g., [18]), is a vital process in eubacteria absent in eukaryotes, and consequently it represents a good target for antibiotics. Among the PG-targeting antibiotics, lipid II binders have been the most exploited [17]. Although lipid II molecules constitute a small fraction of cell-membrane phospholipids [19], their role is essential for the PG biosynthesis and turnover [20]. Such lipid II-binding NRPs as glycopeptide antibiotics (GPAs), vancomycin, and teicoplanin represent the “last defense line” antibiotics to treat infections caused by multidrug-resistant Gram-positive pathogens [21,22], while nisin (an RiPP) is widely used as a food preserving agent [23].
Among lipid II binders, large cyclic non-ribosomally synthesized lipodepsipeptides such as ramoplanin (Rmp) and enduracidin (End) (as well as some other related compounds, more recently discovered, hereafter referred to as RRLDPs—ramoplanin and related lipodepsipeptides), occupy a special niche [24]. These antibiotics interact with lipid II as dimers, forming stable salt bridges with the pyrophosphate portion and enclosing the polar head of lipid II [25]. RRLDPs exhibit a promising antimicrobial activity spectrum against Gram-positive bacterial pathogens, being more active against Staphylococcus spp. (including the methicillin-resistant mutants) than GPAs and showing no cross-resistance with vancomycin towards vancomycin-resistant enterococci (VRA) [26,27,28]. End has been used as an animal growth promoter for decades in various farm animals [29,30,31,32,33,34,35], and notably no cases of End-resistant isolates have been reported yet, implying that resistance is not easily acquired [32]. Rmp has long been investigated for therapeutic applications in humans, but in vivo animal studies demonstrated that it is not orally absorbed, it is instable in plasma, and poorly tolerated if injected, posing significant hurdles to its clinical development [36]. Orally administered Rmp has been recently reconsidered for the treatment of gastrointestinal infections and has progressed into phase III clinical trials, but there is no recent information about its status [37].
In the last decade, novel RRLDPs have been described, enriching this class of promising potential antibiotics and re-attracting the general interest for their peculiar mode of action in overcoming resistant barriers to the current antibiotics in clinics [38,39,40]. Notably, as in the case of Rmp, most of them are produced by relatively uncommon actinomycetes genera, which are difficult to manipulate genetically and present intriguing challenges in handling and fermentation [38,39]. Sequencing of the corresponding biosynthetic gene clusters (BGCs) might enable comparing the different producing pathways, opening the way for an integrated view of RRLDP biosynthesis. Indeed, numerous aspects of RRLDP biosynthesis remain still unexplored and warrant additional investigations. There is a notable absence of contemporary review articles focusing specifically on RRLDP biosynthesis that summarize all these recent findings. In this review, we aim to update the landscape of RRLDP discovery among the producing actinomycetes, with a special focus on reconstructing and discussing the biosynthetic logics behind RRLDP production, on the basis of BGC comparison of old and novel antibiotics belonging to this class. Herein, we also report the gene-engineering and biotechnological strategies to improve the producing strains and processes, which have been optimized mostly during Rmp and End discovery and development. Although the advances in the chemical synthesis of RRLDPs are not covered by this review, it has to be mentioned that Rmp and its analogues can be produced by synthetic chemistry as an alternative to biological production, e.g., [41]. To this purpose, a recently developed solid-phase peptide synthesis and macrocyclization applied to RRLDPs [42,43] represents a promising and innovative method to efficiently explore their structural activity relationship (SAR). Our hope is that a thorough understanding of these aspects among the different RRLDPs might contribute in the future to the re-purposing of this antibiotic class, re-engineering, and re-designing a new generation of molecules able to tackle the diffusion of resistance in Gram-positive pathogens.

5. Tools for the Genetic and Genomic Engineering of RRLDP Producers

A set of general gene-engineering tools has been employed to manipulate the producers of Rmp and End (Table 1). The expression of genes of interest was achieved in the Rmp-producing strain Actinoplanes sp. SIPI-A.2006 (likely a synonym of ATCC 33076, as mentioned above), employing the φC31-based integrative vector pSET152 [132] (Table 1), where gene expression was driven by the Saccharopolyspora erythraea erythromycin resistance gene promoter (ermEp). The strength of different promoters for gene expression was not experimentally investigated in Rmp-producing Actinoplanes spp.; however, by extrapolating the data obtained for other Actinoplanes spp., the ermEp might not be the optimal choice to achieve a strong constitutive gene expression [133,134] and further investigation would be needed. In End-producing strains of S. fungicidicus, genes were expressed using either integrative pSET152 derivatives (Table 1) or replicative pIJ101 derivatives. In S. fungicidicus strains, ermEp was the most commonly used promoter for gene expression, although the usage of the tetracycline-inducible promoter tcp830 was also reported (Table 1).
Table 1. List of plasmids used for gene expression and knockouts in Rmp and End producers.
Table 1. List of plasmids used for gene expression and knockouts in Rmp and End producers.
Plasmid:Used for:Properties:Reference:
pSET152Gene expression in Actinoplanes sp. SIPI-A.2006 (=ATCC 33076)φC31-based integrative vector[50,112,113,118]
pXY152aGene expression in S. fungicidicus ATCC 21013pSET152 [129] derivative, φC31-based integrative expression vector, gene expression achieved via ermEp promoter[111,135]
pSET152ermEGene expression in S. fungicidicus ATCC 31731 (ATCC 21013 derivative)pSET152 [129] derivative, φC31-based integrative expression vector, gene expression achieved via ermEp promoter[123]
pIJ86Gene expression in S. fungicidicus ATCC 21013Replicative expression vector, pIJ101 [136] derivative, gene expression achieved via ermEp promoter[119,137]
pMS17Gene expression in S. fungicidicus ATCC 21013φC31-based integrative expression vector, gene expression achieved via tetracycline-inducible promoter tcp830[119,138]
pXY300Gene knockouts in S. fungicidicus ATCC 21013 via homologous recombinationpGM160 [139] derivative carrying oriT from pOJ446 [132], thermosensitive pSG5 replicon-based replicative vector[111,140]
pKC1139Gene knockouts in Actinoplanes sp. SIPI-A.2006 (=ATCC 21013), A. ramoplaninifer ATCC 21013, and S. fungicidicus TXX3120 (industrial End producer) via homologous recombinationThermosensitive pSG5 replicon-based replicative vector[50,112,118,132]
pHZ1358Gene knockouts in S. atrovirens MGR140 via homologous recombinationReplicative cos-site-containing pIJ101 [136] derivative, unstable and prone to chromosomal integration via homologous recombination[40,141]
pCIMt005Gene knockouts in S. fungicidicus ATCC 31731 (ATCC 21013 derivative) via homologous recombinationThermosensitive pSG5 replicon-based replicative vector, derivative of pBlueScript II KS (+), carrying indigoidine synthetase cassette (Streptomyces lavendulae CGMCC 4.1386 gene idgS co-expressed with Bacillus subtilis phosphopantetheinyl transferase gene sfp using ermEp) [142] and pUWL201PW [143] oriT; as the presence of indigoidine synthetase cassette leads to accumulation of blue indigoidine, application of pCIMt005 simplifies the screening of mutants (where the cassette is lost)[123,142]
Gene knockouts in ramoplanin-producing Actinoplanes spp. were achieved using an approach based on homologous recombination-mediated double crossing-over events [144]. For this purpose, thermosensitive pSG5 replicon-based vectors, replication of which is restricted at 37 °C, allowing homologous recombination into the chromosome [145], were utilized (Table 1). Similarly, pSG5 replicon-based vectors were used for gene knockouts in S. fungicidicus ATCC 21013, ATCC 31731, and TXX3120 (Table 1), while a pIJ101 derivative was employed for knocking out genes in End-producing S. atrovirens MGR140. Notably, CRISPR-Cas9-mediated gene knockouts have recently been performed in S. fungicidicus ATCC 31731 [123].
Intergeneric conjugation, utilizing Escherichia coli ET12567 strains as donors, was employed to deliver plasmid DNA to Rmp- and End-producing strains (see references in Table 1). In the case of End-producing Streptomyces spp., spores were used as recipients. However, the method of conjugal transfer in Rmp-producers remains unclear, as sporangia formation in A. ramoplaninifer ATCC 21013 occurs extremely rarely [48].

6. Ways and Approaches to Improve RRLDP Production in Actinomycetes

Significant effort has been put into optimization and improvement of Rmp and End production during the different phases of their discovery and development. In the case of Rmp, different reports described medium optimization, while for End strategies such as random mutagenesis and rational gene-engineering were published, in combination with medium optimization (Table 2). Although several media previously used for Rmp and End production were tested in M. chersina DSM 44151, chersinamycin production was only detected in H881 medium, which is typically used for dynemicin production [38,59,146] (Table 2). Chersinamycin production was reported only after a prolonged cultivation period (288 h). Although the exact productivity is not clear, ca. 1–3 mg/L of chersinamycin was obtained after purification [38].
Improvement of Rmp production. Initial reports described Rmp production on a fermenter scale, achieving over 60 mg/L of the complex after 60 h of cultivation (Table 2) [47]. Medium optimization led to the formulation of PB-medium described in [147] (Table 2). It was possible to achieve more than 100 mg/L of Rmp (factors A1-3 combined) in PB after 96 h of cultivation. Furthermore, the addition of 5 g/L of l-leucine significantly increased Rmp production to over 400 mg/L. This specifically enhanced the biosynthesis of the A2 factor, which then contributed to more than 96% of the total complex. Such a result was achievable because l-leucine is the precursor of the 7-methylocta-2,4-dienoyl aliphatic side chain of Rmp A2 [147]. Furthermore, addition of 5 g/L of l-valine induced Rmp A3 production to become dominant in the complex, as this amino acid serves as a precursor of the 9-methyldeca-2,4-dienoyl chain. However, in this scenario, the total Rmp production was similar to that in the non-modified medium [147]. A more recent report demonstrated that Rmp production could also be improved by substituting soybean meal in PB with meat-bone meal (>200 mg/L at 168 h of cultivation), poultry meal (>350 mg/L, 168 h), and fish meal (>400 mg/L, 164 h) [148].
Table 2. Media used for the fermentative production of Rmp and End and maximum antibiotic production achieved.
Table 2. Media used for the fermentative production of Rmp and End and maximum antibiotic production achieved.
Antibiotic:Producer Strain:Vegetative Medium Composition (g/L):Production Medium Composition (g/L):Maximal Yield Achieved:Reference:
RmpA. ramoplaninifer ATCC 33076Meat extract—3; Yeast extract—5; Tryptone—5; Soluble starch—24; Glucose—1; CaCO3—4Soybean meal—30; Glucose—40; CaCO3—1>60 h, >60 mg/L[47]
A. ramoplaninifer ATCC 33076Glucose—12; Soluble starch—13; Soybean meal—13; CaCO3—4PB medium
Glucose—4; Maltose—20; Starch—4; Glycerol—20; Sucrose—20; Soybean meal—30; CaCO3—6		96 h, >100 mg/L[147]
ChersinamycinM. chersina DSM 44151Fish meal—10, dextrin—30; lactose—10; CaSO4—6; CaCO3—5H881
Starch—10; Pharmamedia—5; CaCO3—1; CuSO4—0.05; NaI—0.5		288 h, 1–3 mg/L after the purification[38]
EndS. fungicidicus B-5477Not reportedCorn steep liquor—30; Glucose—20; Soluble starch—30; NaCl—5; CaCO3—10120 h, 170 mg/L[28,111]
S. fungicidicus B-5477Corn steep liquor—35; Corn flour—25; Corn gluten meal—5; CaCO3—30; Actocol antifoam—0.5Medium A
Corn flour—80; Corn gluten meal—30; Corn steep liquor—5; NaCl—1; (NH4)2SO4—3; ZnCl2—0.1; Lactose—10; Chicken oil—14; Potassium lactate—5		192 h, 550 mg/L[149]
S. fungicidicus B-5477Corn steep liquor—35; Corn flour—25; Corn gluten meal—5; CaCO3—30; Actocol antifoam—0.5Medium B
Corn flour—50; Corn gluten meal—40; Corn steep liquor—5; Na2H2PO4—26; NaCl—5; (NH4)2SO4—3; ZnCl2—0.1; Lactose—10; Chicken oil—14; Potassium lactate—1		192 h, 530 mg/L[149]
EndS. fungicidicus SG-01Glucose—30, Corn steep liquor—30, Yeast extract—5; Ca2CO3—20; NaCl—8Glucose—40; Soluble starch—40; Corn steep liquor—20; Corn gluten meal—30; NaCl—15; NH4Cl—5; Ca2CO3—15240 h, ca. 300 mg/L[52]
EndS. fungicidicus ATCC 31731Corn steep liquor—35; Corn starch—30; Glucose—20; CaCO3—20Sucrose—100; Glucose—10; Casamino acids—0.1; Yeast extract—5; MOPS—21; K2SO4—0.25; MgCl2—10; MnSO4—1 × 10−3; CuSO4—0.5 × 10−3; ZnSO4—1 × 10−3; CoCl2—1192 h, 740 mg/L[123]
EndS. fungicidicus TXX3120Corn flour—35; Corn steep liquor—28; Cottonseed meal—5; (NH4)2SO4—5; FeSO4—0.36; KH2PO4 1.25; Light calcium carbonate—5; Olive oil—0.5 mL/LCorn flour—80; Soybean flour—28; (NH4)2SO4—4; Corn steep liquor—20; Glucose monohydrate—6; FeSO4—0.1; L-lactic acid—2; Light CoCO3—5; Thermostable α-Amylase—1500 IU/L; Soybean oil—0.5 mL/L144 h, ca. 4000 U/mL[51]
EndS. atrovirens MGR140Not reportedSoluble starch—30; Soybean meal—10; Glucose—20; Yeast powder—10; CaCO3—10; NaCl—5Not reported, ca. 40 mg/L[55]
EndStreptomyces sp. MC079Glucose—20; Yeast extract—3; Peptone—2; FeSO4—0.1; K2HPO4—2; NaCl—10Glucose—40; Peptone—5; FeSO4—0.1; K2HPO4—2; NaCl—10160 h, 35 mg/L[56]
Improvement of End production. The very first report in 1968 explored the dependence of End production on nitrogen and carbon sources in a basal medium [28]. The utilization of optimal nitrogen (corn steep liquor) and carbon (soluble starch combined with glucose) sources (Table 2) led to an End production of 170 mg/L in S. fungicidicus B-5477. Consequently, two other optimized media (A and B, Table 2), designed for End production in mutants (see below), also supported higher production in B-5477, yielding ca. 500 mg/L of the antibiotic [149]. UV-mutagenesis, selection of 3-fluoro-d,l-tyrosine-resistant mutants, and the combination of both methods were then applied to B-5477. Mutant obtained through UV-mutagenesis (named GAB-453) produced up to 1.730 g/L End in an optimized medium A [149]. Additionally, 2.56 g/L of End were produced by 3-fluoro-d,l-tyrosine-resistant mutant (Emt 36-3) in the optimized medium B. Finally, GAB-453 itself was used as a starting point to generate 3-fluoro-d,l-tyrosine-resistant mutant (Emt 2-140), which was able to produce a striking 4.34 g/L End in medium B [149].
A combined approach was used later to enhance End production in S. fungicidicus L-69 [53]. Although there is no information about the origin of L-69, its unusually high reported End-production level (ca. 1 g/L) suggests that L-69 might already be a product of an undisclosed mutagenesis process. In the first stage of mutagenesis, L-69 spores were treated with atmospheric and room temperature plasma (ARTP) to obtain streptomycin-resistant mutants (using a selection concentration of 20 mg/L streptomycin). The best-producing mutant from this stage yielded ca. 1.37 g/L of End and was subjected to a second mutagenesis step [53]. At this stage, spores of the previous mutant were treated with Cesium-137 γ-radiation and plated on a medium with an increased streptomycin concentration (50 mg/L). The top-producing mutant from this second stage exhibited an End production at the level of ca. 1.58 g/L [53]. Unfortunately, the composition of the production medium used here is unclear. Later, carbon ion radiation-induced mutagenesis was applied to another S. fungicidicus SG-01 [52], whose origin is unclear. Its reported End-production level (ca. 300 mg/L after 240 h of cultivation) hints that SG-01 might be also a wild-type strain, possibly a synonym of ATCC 21013. This mutagenesis approach yielded several mutants with significantly improved End production, reaching up to ca. 600 mg/L [49]. Notably, the addition of 10 g/L of l-arginine improved End production in an SG-01-derived mutant, though the effect was not tested in the initial strain [52]. End-overproducers obtained through random mutagenesis, as discussed above, were shown to gradually lose their elevated production levels [52,53].
A recombinant approach using the tools described in the previous section was used for S. fungicidicus ATCC 31731 (End high-producer derived from ATCC 21013 through random mutagenesis) [123]. In this case, genes coding for positive regulators of End biosynthesis (discussed in Section 4.6)—an StrR-like PSR (end22) and a sensor-histidine kinase (end42)—were overexpressed in ATCC 31731 using a pSET152 derivative with ermEp (see above) [123]. Although ATCC 31731 already produced a significant amount of End (ca. 0.8 g/L) in a variation of R5 medium [123,144], end22 overexpression increased the production to ca. 3 g/L, while the overexpression of end42 led to a production of ca. 1.7 g/L.
Another approach combining gene-engineering and random mutagenesis was applied to another industrial End-producer, S. fungicidicus TXX3120 [51]. Here, the expression levels of end genes were first assessed in TXX3120, identifying the endC NRPS gene as the least expressed [51]. It was thus hypothesized that endC expression could be a bottleneck for enduracidin production. The 5′-region of endC was substituted with tsr thiostrepton resistance gene. The recombinant strain then underwent ARTP mutagenesis to select for mutants with increased resistance to thiostrepton, suggesting that such mutants might carry beneficial mutations (e.g., in regulatory genes, promoter of the putative end15-A-B-C-16-D operon, etc.) that enhance tsr expression [51]. Subsequently, in several mutants with increased thiostrepton resistance, tsr was reverse-substituted with the 5′-terminal region of endC, restoring End production. As a result, these strains showed increased endC expression, and enduracidin production was enhanced by approximately two-fold, although the exact quantity is difficult to ascertain since the production was reported in U/mL [51].
Very low levels of End production were detected in the environmental strains recently reported [40,55,56]. In S. atrovirens MGR140, End was initially detected in a non-optimized TSB medium, but production rates under these conditions were not reported [40]. An optimized medium was used in subsequent experiments (Table 2), where End production ranged from 30 to 50 mg/L [55]. Finally, spontaneous streptomycin-resistance mutants of S. atrovirens MGR140 with increased End production levels were obtained [55]. Lastly, another combination of media was employed for End production in Streptomyces sp. MC079, yielding ca. 35 mg/L of antibiotic after 160 h of cultivation [56]. Continuous control of pH during cultivation increased production to 40 mg/L (pH 5.5) and 46 mg/L (pH 5.8). A two-stage pH shift (pH 5.5 changed to pH 5.8 after 112 h of cultivation) further increased End production to ca. 53 mg/L [56].

7. Conclusions and Outline

Different aspects of the biology and chemistry of RRLDPs have been updated in recent decades. For instance, the mode of action of Rmp and End as lipid II binders has been clarified and reviewed after being the subject of intensive debate for a long time [24,25,150,151]. Additionally, the same reviews exhaustively covered the reports on chemical synthesis of RRLDPs [24,35], e.g., a total synthesis of Rmp A2 and ramoplanose aglycon [41], and a recent publication has described the advances in peptide synthesis using solid phase to prepare arylglycine-containing peptides including Rmp analogs [42], providing a new insight into SAR of RRLDPs. However, none of these reports investigated the growing body of evidence concerning the genetic background of RRLDP biosynthesis, the mechanisms involved in their biosynthesis, or the production conditions in various strains in vivo.
In this review, we focused on these topics, integrating the biosynthetic picture for different RRLDPs, comparing the available BGCs, and reviewing where the roles of different genes and enzymes have been experimentally confirmed or postulated by homology. The aim was to gain insight into the complex biosynthetic machinery behind the production of these NRP antibiotics and to offer an overview of the different tools (including genetic engineering approaches and cultivation media) used to study and enhance their biological production.
Most of the information available today has been derived from studies on Rmp and End due to their historical significance as a clinical antibiotic candidate and as an animal growth promoter, respectively. Nevertheless, recent experimental screening [39] and genome mining efforts [38] have demonstrated that many other RRLDPs likely exist in nature beyond Rmp and End, with the first newly discovered compound being chersinamycin [38]. Additionally, the growing diversity of RRLDP BGC sequences opens the door to combining different pathways to generate novel RRLDPs. Taken together, these opportunities renew interest in this class of antibiotics and establish the way for their further development.
Another intriguing aspect highlighted in this review, as well as in other recent works [97,121,152], is that RRLDP BGCs share phylogenetic relationships with GPA BGCs. GPAs also belong to the class of NRP antibiotics that bind lipid II. For example, recent work on the heterologous expression of the CSRG regulator from M. chersina DSM 44151—chers28, a StrR-like PSR—enhanced the production of the valuable GPAs teicoplanin and A40926 in A. teichomyceticus NRRL B-16726 and N. gerenzanensis ATCC 39727, respectively. In contrast, overexpression of ramo5 (coding for the chers28 orthologue) had no such effect [122].
The application of either native CSRGs (as demonstrated for End production in S. fungicidicus ATCC 31731 [123]) or heterologous CSRGs (yet to be tested) appears to be one of the most promising strategies to improve RRLDP production. For example, A. ramoplaninifer ATCC 33076, a producer of Rmp, would certainly benefit from this type of investigation. Alternatively, these regulators could be used to activate seemingly silent RRLDP BGCs, following the approaches applied in GPAs [117,153].
By combining these various approaches, it may be possible to elevate RRLDPs into a clinically successful class of NRP antibiotics, which could potentially help in overcoming the spread of multidrug-resistant Gram-positive pathogens in the future. We hope that this review might ignite such efforts.

Author Contributions

K.Z. and E.B. performed the literature search; O.Y. and E.B. analyzed the literature; O.Y. prepared the figures; and O.Y. and F.M. wrote the original draft. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by an FEMS Ukraine Support Grant to K.Z. (2022), by Fondo Ateneo di Ricerca 2021/2022 to F.M., by Humboldt Research Fellowship for Postdocs from Alexander von Humboldt Foundation to O.Y., and through the EURIZON project, which is funded by the European Union under grant agreement No. 871072 to O.Y.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

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