Comparative Genomics and Metabolomics of Domesticated, Pladienolide-Producing Streptomyces Bacteria

Laboratory domestication of bacteria can negatively affect natural product production. This problem continues to plague discovery and development efforts. In this study, we investigated pladienolides from Streptomyces platensis, synthetic derivatives of which entered clinical trials for the treatment of acute myeloid leukemia. Solid cultures of the deposited S. platensis Mer-11107 yielded black, gray, and white colonies with identical 16S rRNA gene sequences, revealing that they were the same species. Importantly, metabolite analysis identified one white isolate with a 3-fold improvement in pladienolide B titers. Experimental evolution of black isolates gave rise to both gray and white colonies. In contrast, gray and white isolates did not generate the black phenotype, suggesting black isolates are ancestral strains and that the mechanism underlying the phenotypic heterogeneity is irreversible. Comparative genomics revealed sequence and structure variations that may help explain the observed differences in development and metabolite production. The increase in pladienolide titers with the white isolate is in line with the recent concept of division of labor within Streptomyces colonies, where genomic instability results in some cells specializing in antibiotic production and others remaining reproductive. Ultimately, identification of the pladienolide B overproducer will facilitate future studies in this important class of splice-modulating antitumor agents.