Paired Genomic and Metabolomic Analysis Reveals the Secondary Metabolome Potential of Cystobacter

Aims The genus Cystobacter has been reported to produce bioactive secondary metabolites and harbor abundant biosynthetic gene clusters (BGCs). However its genomic and metabolomic potential remains largely unexplored due to the lack of systematic data mining studies. Here, we present the first paired genomic and metabolomic analysis of Cystobacter to uncover its secondary metabolic capabilities. Methods and Results By examining its genomic features and classifying BGC patterns, we provided a comprehensive overview of the biosynthetic capabilities of Cystobacter. Our analysis revealed that 91% of BGCs remain uncharacterized, with ribosomally synthesized and post-translationally modified peptides (RiPPs) being the most predominant class. An in-depth analysis of RiPP core peptides from Cystobacter demonstrated distinct features compared to those from other species, and deep learning models predicted that five of these peptides have antimicrobial potential. As a proof of concept, we integrated the genomic data of Cystobacter ferrugineus Cbfe23 with its metabolomics profile, leading to the correlation of a cluster of novel tubulysin analogs with its biosynthetic pathway. Conclusion This paired genomic and metabolomic analysis reveals the untapped secondary metabolic potential of Cystobacter, highlighting its important roles in drug discovery, microbial communities, and bioengineering.