Contributed Poster Abstract
Biosynthesis of thiocarboxylic acid-containing natural products in bacteria
Liaobin Dong1, Jeffrey Rudolf2, Dr. Nan Wang2 and Ben Shen3, (1)Department of Chemistry, The Scripps Research Institute, Jupiter, FL, USA, (2)The Scripps Research Institute, Jupiter, FL, USA, (3)Department of Chemistry, Department of Molecular Medicine, Natural Products Library Initiative at The Scripps Research Institute, The Scripps Research Institute, Jupiter, FL, USA
Natural Product Discovery and Development in the Genomic Era
Thiocarboxylate acid-containing natural products are rare and their biosynthesis and biological significance remain unknown. Thiocarboxylate analogues of platensimycin (PTM) and platencin (PTN), antibacterial natural products, were recently discovered. Here, we report the identification of a “thioacid cassette” encoding two proteins, PtmA3 and PtmU4, responsible for carboxylate activation by coenzyme A (CoA) and sulfur transfer, respectively. Gene inactivation of ptmA3, ptmU4, and genes encoding the sulfur-carrier protein system in the PTM–PTN overproducing strain SB12029 revealed their roles in thioPTM and thioPTN production, supporting thioPTM and thioPTN as the bona fide products of the ptm and ptn biosynthetic gene clusters. Both thioPTM and thioPTN retained strong antibacterial activities and bind tightly to FabF and FabH, the fatty acid biosynthesis targets of PTM and PTN. The thioacid cassette is prevalent in the genomes of bacteria, implicating that thiocarboxylate acid-containing natural products are an underappreciated class of natural products. The broad substrate promiscuity of the thioacid cassette provides opportunities to generate libraries of thioacids for future drug discovery efforts.