S23: The biosynthesis of nucleoside antibiotics targeting bacterial translocase I

New antibiotics are needed to overcome the rapid emergence or drug-resistant strains. We have developed a screen aimed at identifying novel antibiotics that are inhibitors of a previously unexploited cellular target, bacterial translocase I, which is an essential enzyme involved in peptidoglycan cell wall biosynthesis. This screen has led to the discovery of several uridine-based nucleoside antibiotics produced by various actinomycetes, the most prolific source of antibacterial agents. We have now identified the biosynthetic genes for five of these translocase I inhibitors, and our biochemical studies have unearthed rich chemistry with several interesting transformations highlighted by (i) an ATP-independent mechanism of amide bond formation, (ii) a novel sugar biosynthetic pathway that originates from uridine-5’-monophosphate, and (iii) a previously unknown mechanism of resistance of covalent modification by an arylsulfotransferase. These results, along with how the biochemical knowledge has been utilized to generate novel analogues and the potential of these metabolites as antibiotics, will be presented.