Uncovering the biosynthetic potential of Amycolatopsis: new insights into glycopeptide antibiotic and polyketide gene clusters

Abstract

Background: : Amycolatopsis species are renowned producers of a vast array of biologically active molecules, including Glycopeptide antibiotics (GPAs), polyketides, siderophores, and terpenes. Despite their clinical significance, the full biosynthetic genetic capacity and evolutionary diversification of Amycolatopsis remain unexplored. Methods and Results: We analyzed 16 Amycolatopsis strains, including six newly sequenced in this work, six from our previously published datasets, and four retrieved from NCBI. Phylogenetic, pangenome, and antiSMASH-based genome-mining analyses were performed to identify secondary metabolite gene clusters, with a focus on NRPS, PKS, terpenes, and siderophores. Conserved glycopeptide gene clusters found across Cluster A strains, encoding core NRPSs, P450 oxygenases, and tailoring enzymes with variations consistent with the structural GPA types. Analysis showed conserved but distinct GPA BGC organization corresponding to the type I, II, and III subclasses, as well as their genetic, structural, and functional diversifications. A. azurea DSM 43854T produced A35512B rather than azureomycins, while A. alba DSM 44262T produced vancomycin. Six previously unreported Cluster A strains were found to encode putative GPA gene clusters, and LC–MS profiling predicted GPA production of nogabecin from A. keratiniphila subsp. keratiniphila DSM 44409T and A33512B from A. thailandensis JCM 16380T. GPA biosynthetic capacity was largely restricted to Cluster A, but in Cluster C, in the case of A. balhimycina DSM 44591T. Type II PKS, siderophore, and terpene gene clusters were also explored for these strains. Conclusions: This study provides a comparative genomic overview of Amycolatopsis Cluster A, highlighting GPA diversity and revealing broader potential for secondary metabolites.