Discovering the secondary metabolic potential of Saccharothrix.

Rare actinomycetes are highly valued as potential sources of novel bioactive secondary metabolites. Among these rare actinomycetes, the genus Saccharothrix is particularly noteworthy due to its ability to produce a diverse range of bioactive secondary metabolites. With the continuous sequencing of bacterial genomes and the rapid development of bioinformatics technologies, our knowledge of the secondary metabolic potential of Saccharothrix can become more comprehensive, but this space has not been reviewed or explored. This review presents a detailed overview of the chemical structures and bioactivities of 138 Saccharothrix-derived secondary metabolites, which are classified into five distinct groups based on their biosynthetic pathways. Furthermore, we delve into experimentally characterized biosynthetic pathways of nine bioactive metabolites. By utilizing a combination of cheminformatic and bioinformatic approaches, we attempted to establish connections between the metabolite families and the biosynthetic gene cluster families encoded by Saccharothrix strains. Our analysis provides a comprehensive perspective on the secondary metabolites that can be linked to corresponding BGCs and highlights the underexplored biosynthetic potential of Saccharothrix. This review also provides guidance for the targeted discovery and biosynthesis of novel natural products from Saccharothrix.

Species-specificity of the secondary biosynthetic potential in Bacillus.

Introduction: Although Bacillus species have produced a wide variety of structurally diverse and biologically active natural products, the secondary biosynthetic potential of Bacillus species is widely underestimated due to the limited number of biosynthetic gene clusters (BGCs) in this genus. The significant variation in the diversity and novelty of BGCs across different species within the Bacillus genus presents a major obstacle to the efficient discovery of novel natural products from Bacillus. Methods: In this study, the number of each class of BGCs in all 6,378 high-quality Bacillus genomes was predicted using antiSMASH, the species-specificity of BGC distribution in Bacillus was investigated by Principal component analysis. Then the structural diversity and novelty of the predicted secondary metabolites in Bacillus species with specific BGC distributions were analyzed using molecular networking. Results: Our results revealed a certain degree of species-specificity in the distribution of BGCs in Bacillus, which was mainly contributed by siderophore, type III polyketide synthase (T3PKS), and transAT-PKS BGCs. B. wiedmannii, B. thuringiensis, and B. cereus are rich in RiPP-like and siderophore BGCs, but lack T3PKS BGCs, while B. amyloliquefaciens and B. velezensis are abundant in transAT-PKS BGCs. These Bacillus species collectively encode 77,541 BGCs, with NRPS and RiPPs being the two most dominant types, which are further categorized into 4,291 GCFs. Remarkably, approximately 54.5% of GCFs and 93.8% of the predicted metabolite scaffolds are found exclusively in a single Bacillus species. Notably, B. cereus, B. thuringiensis, and B. velezensis exhibit the highest potential for producing species-specific NRPS and PKS bioinformatic natural products. Taking two species-specific NRPS gene clusters as examples, the potential of Bacillus to synthesize novel species-specific natural products is illustrated. Conclusion: This study highlights the species-specificity of the secondary biosynthetic potential in Bacillus and provides valuable insights for the targeted discovery of novel natural products from this genus.

Global analysis of the biosynthetic chemical space of marine prokaryotes.

BACKGROUND: Marine prokaryotes are a rich source of novel bioactive secondary metabolites for drug discovery. Recent genome mining studies have revealed their great potential to bio-synthesize novel secondary metabolites. However, the exact biosynthetic chemical space encoded by the marine prokaryotes has yet to be systematically evaluated. RESULTS: We first investigated the secondary metabolic potential of marine prokaryotes by analyzing the diversity and novelty of the biosynthetic gene clusters (BGCs) in 7541 prokaryotic genomes from cultivated and single cells, along with 26,363 newly assembled medium-to-high-quality genomes from marine environmental samples. To quantitatively evaluate the unexplored biosynthetic chemical space of marine prokaryotes, the clustering thresholds for constructing the biosynthetic gene cluster and molecular networks were optimized to reach a similar level of the chemical similarity between the gene cluster family (GCF)-encoded metabolites and molecular family (MF) scaffolds using the MIBiG database. The global genome mining analysis demonstrated that the predicted 70,011 BGCs were organized into 24,536 mostly new (99.5%) GCFs, while the reported marine prokaryotic natural products were only classified into 778 MFs at the optimized clustering thresholds. The number of MF scaffolds is only 3.2% of the number of GCF-encoded scaffolds, suggesting that at least 96.8% of the secondary metabolic potential in marine prokaryotes is untapped. The unexplored biosynthetic chemical space of marine prokaryotes was illustrated by the 88 potential novel antimicrobial peptides encoded by ribosomally synthesized and post-translationally modified peptide BGCs. Furthermore, a sea-water-derived Aquimarina strain was selected to illustrate the diverse biosynthetic chemical space through untargeted metabolomics and genomics approaches, which identified the potential biosynthetic pathways of a group of novel polyketides and two known compounds (didemnilactone B and macrolactin A 15-ketone). CONCLUSIONS: The present bioinformatics and cheminformatics analyses highlight the promising potential to explore the biosynthetic chemical diversity of marine prokaryotes and provide valuable knowledge for the targeted discovery and biosynthesis of novel marine prokaryotic natural products. Video Abstract.

Secondary Metabolic Potential of Kutzneria.

Kutzneria is a rare genus of Actinobacteria that harbors a variety of secondary metabolite gene clusters and produces several interesting types of bioactive secondary metabolites. Recent efforts have partially elucidated the biosynthetic pathways of some of these bioactive natural products, suggesting the diversity and specificity of secondary metabolism within this genus. Here, we summarized the chemical structures, biosynthetic pathways, and key metabolic enzymes of the secondary metabolites isolated from Kutzneria strains. In-depth comparative genomic analysis of all six available high-quality Kutzneria genomes revealed that the majority (77%) of the biosynthetic gene cluster families of Kutzneria were untapped and identified homologues of key metabolic enzymes in the putative gene clusters, including cytochrome P450s, halogenases, and flavin-dependent N-hydroxylases. The present study suggests that Kutzneria exhibits great potential to synthesize novel secondary metabolites, encodes a variety of valuable metabolic enzymes, and also provides valuable information for the targeted discovery and biosynthesis of novel natural products from Kutzneria.

Non-ribosomal peptide biosynthetic potential of the nematode symbiont Photorhabdus.

Photorhabdus, the symbiotic bacteria of Heterorhabditis nematodes, has been reported to possess many non-ribosomal peptide synthetase (NRPS) biosynthesis gene clusters (BGCs). To provide an in-depth assessment of the non-ribosomal peptide biosynthetic potential of Photorhabdus, we compared the distribution of BGCs in 81 Photorhabdus strains, confirming the predominant presence (44.80%) of NRPS BGCs in Photorhabdus. All 990 NRPS BGCs were clustered into 275 gene cluster families (GCFs) and only 13 GCFs could be annotated with known BGCs, suggesting their great diversity and novelty. These NRPS BGCs encoded 351 novel peptides containing more than four amino acids, and 173 of them showed high sequence similarity to known BGCs encoding bioactive peptides, implying the promising potential of Photorhabdus to produce valuable peptides. Sequence similarity networking of adenylation (A-) domains suggested that the substrate specificity of A-domains was not directly correlated with the sequence similarity. The molecular similarity network of predicted metabolite scaffolds of NRPS BGCs and reported peptides from Photorhabdus and a relevant database demonstrated that the non-ribosomal peptide biosynthetic potential of Photorhabdus was largely untapped and revealed the core peptides deserving intensive studies. Our present study provides valuable information for the targeted discovery of novel non-ribosomal peptides from Photorhabdus.