Organic Chemistry Seminar

Since peptidoglycan (PG) and cell walls are essential bacterial polymers, the machinery for cell wall biosynthesis provides a unique and selective target for antibiotic action.  The majority of the components of the pathway have been extensively characterized biochemically and structurally except for the membrane-associated components.  Translocase I (phospho-N-acetylmuramoyl-pentapeptide-transferase), a phosphotransferase, is an essential enzyme that catalyzes the transfer of UDP-N-acetyl-muramoyl-pentapeptide (Park's nucleotide) to form prenyl-diphosphoryl N-acetyl-muramoyl-pentapeptide (lipid I).  A number of selective translocase I inhibitors of nucleoside antibiotics have been reported.  We have led in the development of natural product based inhibitors for translocase I.  In a large part, efforts have focused on compounds that specifically target Mycobacterium tuberculosis (Mtb); however, all of the developed tools are also used to study other pathogens (MRSA, Clostridium difficile, Klebsiella pneumonia, Pseudomonas aeruginosa, and Acinetobacter baumannii).  A fundamental problem in the treatment of TB is the long duration of therapy required to cure patients leading to increased risk of resistance.  Currently, several capuramycin and muraymycin analogs have been identified that killed non-replicating Mtb at low concentrations by targeting the other phosphotransferase, GlcNAc-1-phosphate transferase (WecA) at nanomolar concentrations.  The efficacy of new nucleoside antibiotics against non-replicating bacteria is especially important, suggesting that at least some cell wall biosynthesis is necessary to maintain viability of Mtb in a latent (dormant) state.