Planta Med 2012; 78 - CL3
DOI: 10.1055/s-0032-1320238

The discovery and biosynthesis of nucleoside antibiotics Inhibiting cell wall assembly

SG Van Lanen 1
  • 1College of Pharmacy, University of Kentucky, 789 S. Limestone, Lexington KY 40536, USA

The emergence of multidrug resistant bacteria has detrimentally impacted the clinical utility of several antibiotics, resulting in predictions that many previously first-line antibiotics will be rendered useless in the near future. This problem is compounded by the steady decline in the FDA approval of antibacterial drugs, particularly those considered new molecular entities. These alarming trends have provided the inspiration to search for the next generation of antibiotics, particularly those with new chemical features and/or new modes of action. 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.