An engineered biosynthetic-synthetic platform for production of halogenated indolmycin antibiotics

Abstract

Indolmycin is an antibiotic fromStreptomyces griseusATCC 12648 with activity againstHelicobacter pylori,Plasmodium falciparum, and methicillin-resistantStaphylococcus aureus. Here we describe the use of the indolmycin biosynthetic genes inE. colito make indolmycenic acid, a chiral intermediate in indolmycin biosynthesis, which can then be converted to indolmycin through a three-step synthesis. To expand indolmycin structural diversity, we introduce a promiscuous tryptophanyl-tRNA synthetase gene (trpS) into ourE. coliproduction system and feed halogenated indoles to generate the corresponding indolmycenic acids, ultimately allowing us to access indolmycin derivatives through synthesis. Bioactivity testing against methicillin-resistantStaphylococcus aureusshowed modest antibiotic activity for 5-, 6-, and 7-fluoro-indolmycin.