Microcin C: biosynthesis and mechanisms of bacterial resistance

Nonhydrolyzable aminoacyl-adenylates that inhibit protein synthesis provide a promising route towards the development of novel antibiotics whose mechanism of action limits the appearance of bacterial drug resistance. The 'Trojan horse' antibiotic microcin C (McC) consists of a nonhydrolyzable aspartyl-adenylate that is efficiently imported into bacterial cells owing to a covalently attached peptide carrier. Once inside the cell, the carrier is removed by proteolytic processing to release a potent aspartyl tRNA synthetase inhibitor. The focus of this article is on the mechanism of biosynthesis of McC. We also examine the strategies utilized by McC-producing strains to overcome toxicity due to unwanted, premature processing of the drug. This article will discuss how McC biosynthesis can be systematically manipulated for the development of derivatives that will target the entire battery of aminoacyl tRNA synthetases in various bacteria.