Characterization of the Ohmyungsamycin Biosynthetic Pathway and Generation of Derivatives with Improved Antituberculosis Activity

Abstract

The cyclic depsipeptides ohmyungsamycin (OMS) A (<b>1</b>) and B (<b>2</b>), isolated from the marine-derived <i>Streptomyces</i> sp. SNJ042, contain two non-proteinogenic amino acid residues, <i>β</i>-hydroxy-l-phenylalanine (<i>β</i>-hydroxy-l-Phe) and 4-methoxy-l-tryptophan (4-methoxy-l-Trp). Draft genome sequencing of <i>Streptomyces</i> sp. SNJ042 revealed the OMS biosynthetic gene cluster consisting of a nonribosomal peptide synthetase (NRPS) gene and three genes for amino acid modification. By gene inactivation and analysis of the accumulated products, we found that OhmL, encoding a P450 gene, is an l-Phe <i>β</i>-hydroxylase. Furthermore, OhmK, encoding a Trp 2,3-dioxygenase homolog, and OhmJ, encoding an <i>O</i>-methyltransferase, are suggested to be involved in hydroxylation and <i>O</i>-methylation reactions, respectively, in the biosynthesis of 4-methoxy-l-Trp. In addition, the antiproliferative and antituberculosis activities of the OMS derivatives dehydroxy-OMS A (<b>4</b>) and demethoxy-OMS A (<b>6</b>) obtained from the mutant strains were evaluated in vitro. Interestingly, dehydroxy-OMS A (<b>4</b>) displayed significantly improved antituberculosis activity and decreased cytotoxicity compared to wild-type OMS A.