A Novel Strategy for Developing New Antibiotics Against Klebsiella with High Barriers to Resistance

Rebecca Page and her team at the University of Connecticut Health Center in the U.S. are developing a new class of antibiotic to target Klebsiella species. This strategy leverages their recent discovery that key steps in the formation of the bacterial cell wall, peptidoglycan recruitment and crosslinking, occur at different sites in penicillin binding proteins (PBPs). Their team will use an integrated approach combining sophisticated NMR spectroscopy, X-ray crystallography, high-throughput fragment screening, substrate synthesis, biochemistry and biophysics to identify the specific residues in Klebsiella PBPs responsible for peptidoglycan recruitment. They will then identify novel chemical matter that target these sites. This new class of antibiotics is predicted to have an exceptionally high barrier to resistance because mutations that inhibit antibiotic binding will also inhibit substrate recruitment and, in turn, the formation of the bacterial cell wall.

This grant is funded by The Novo Nordisk Foundation.