Discovery of 16-Demethylrifamycins by Removing the Predominant Polyketide Biosynthesis Pathway in Micromonospora sp. Strain TP-A0468

摘要: A number of strategies have been developed to mine novel natural products based on biosynthetic gene clusters and there dozens successful cases facilitated by the development genomic sequencing. During our study biosynthesis antitumor polyketide kosinostatin (KST), we found that genome Micromonospora sp. strain TP-A0468, producer KST, contains other potential clusters, with no encoded detected. Deletion kst cluster led abolishment KST enrichment several new compounds, which were isolated characterized as 16-demethylrifamycins (referred here compounds 3 6). Transcriptional analysis demonstrated expression essential genes related 6 was comparable level in wild-type deletion strain. This indicates accumulation these due redirection metabolic flux rather than transcriptional activation. Genetic disruption, chemical complementation, bioinformatic revealed production accomplished cross talk between two distantly placed pks3 M-rif finding not only enriches analogue pool diversity rifamycins but also provides an auxiliary strategy for product discovery through mining polyketide-producing microorganisms.IMPORTANCE Natural are clinically used drugs. Discovering modifying known still main ways generate candidates. Here, discovered varied skeleton structures redirecting from predominant pathway rifamycin marine actinomycetes species TP-A0468. Rifamycins indispensable chemotherapeutics treatment various diseases such tuberculosis, leprosy, AIDS-related mycobacterial infections. exemplifies a useful method cryptic genome-sequenced microbes. Moreover, their genetically manipulable provide opportunity construction derivates aid defense against ever-growing drug resistance Mycobacterium tuberculosis.