Metabolic blockade-based genome mining of Streptomyces cacaoi SCSIO 68063: Isolation and identification of BE-18257 and pentaminomycin analogues

Whole-genome sequencing and bioinformatics analyses have shown that the potential of synthesizing secondary metabolites from marine-derived Streptomyces has been substantially underestimated. In this study, genome analysis of marine-derived Streptomyces cacaoi SCSIO 68063 revealed the presence of a putative biosynthetic gene cluster (BGC, termed sca herein) responsible for biosynthesis of two sets of structurally distinct cycolpeptides, BE-18257 and pentaminomycins. Application of one strain many compounds (OSMAC) strategy to strain SCSIO 68063 only led to the production of BE18257 A-C (1-3). PCR-targeted inactivation of the NRPSs associated with BE-18257 enabled the mutant strain of SCSIO 68063 to biosynthesize pentaminomycins B-E and H (6-9 and 12). In addition, scaP, a previously un-reported ABC transporter gene in the sca cluster, was demonstrated to play an important role in the synthesis of cyclic pentapeptides by in vivo gene disruption experiment. This study showcases a new enabling approach by which to obtain the pentaminomycins; more generally, it paves the way for further biosynthetic investigations and activation of other silent gene clusters.(c) 2022 Elsevier Ltd. All rights reserved.