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 unreported 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.