Studies on the Biological Mechanisms of Antibiotics

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 DESCRIPTION (provided by applicant): Antibiotic resistant bacterial infections pose a serious threat to human health. Resistance is increasing while research into new antibiotics and possible new targets is lagging. Both Gram-positive and Gram-negative bacteria are surrounded by a cross-linked carbohydrate polymer, peptidoglycan (PG). This polymer is essential for bacterial survival because it stabilizes the cell membrane against high internal osmotic pressures. Peptidoglycan biosynthesis is a major target for antibiotics because interfering with this process leads to cell lysis. Indeed, the beta-lactams and glycopeptide antibiotics inhibit PG biosynthesis. Many PG biosynthetic enzymes are already targeted by clinically used antibiotics; however, one class of especially promising targets, the peptidoglycan glycosyltransferases (PGTs), remains unexploited. This research program is focused on discovering inhibitors of PGTs. These enzymes are attractive targets because their functions are essential, their structures are highly conserved in all bacteria, they have no mammalian homologs and they are located on the outer surface of the plasma membrane, which makes them more accessible to inhibitors than intracellular enzymes. The research described here constitutes an integrated, comprehensive program to discover and develop PGT inhibitors using library screening, synthetic organic chemistry, biochemical and cellular assays, structural studies, and bacterial genetics. The proposed work may lead to new compounds to treat antibiotic-resistant infections.