The production of serine ?-lactamase is one of the primary resistance mechanisms used by Gram-negative bacterial pathogens against ?-lactam antibiotics, which include the widely used penicillins and cephalosporins, as well as last resort antibiotics such as the carbapenems. The development of novel ?-lactamase inhibitors is a pressing need underscored by the continuing mutation of ?-lactamases. We propose the development of high affinity non-covalent ?-lactamase inhibitors by targeting conserved structural motifs, particularly those essential for extended spectrum ?-lactamase activity. Prototypes of these inhibitors have already been identified. Specifically, using the CTX-M Class A ?-lactamases as a model system, we aim to: 1) apply a fragment-based and structure-guided approach to develop novel ?-lactamase inhibitor chemotypes;2) study resistance and ligand binding by ultrahigh-resolution and room-temperature X-ray crystallography;and 3) investigate the evolution of resistance mutations against non-covalent inhibitors. These experiments will lead to new ?- lactamase inhibitors with clinical potential, while providing a deeper understanding of ?-lactamase mutations relevant to resistance evolution.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
3R01AI103158-02S1
Application #
8890404
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Xu, Zuoyu
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of South Florida
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Tampa
State
FL
Country
United States
Zip Code
33612
Nichols, Derek A; Renslo, Adam R; Chen, Yu (2014) Fragment-based inhibitor discovery against ?-lactamase. Future Med Chem 6:413-27