-Lactam antibiotics represent the largest and clinically most used family of antibacterial agents. The existence of -lactamases, enzymes capable of destroying -lactams, in Gram-negative bacteria is a serious clinical problem. A subset of these enzymes, carbapenemases, hydrolyzes carbapenem antibiotics avidly. Carbapenems are drugs of last resort in treatment of life-threatening infections. Enzymes with carbapenemase activity have been identified in all four molecular classes of -lactamases (classes A, B, C and D). Class D carbapenemases are widely distributed in Acinetobacter and Enterobacteriaceae isolates that are resistant to other available classes of antibiotics, and these carbapenemase-producing bacteria are often multi-drug or even pan-drug resistant. Infections caused by such pathogens are difficult or sometimes impossible to treat. In this grant proposal we will perform detailed microbiological, kinetics and structural characterization of the major class D carbapenemases of A. baumannii. These enzymes are widely distributed in clinical A. baumannii isolated and have elevated this pathogen to the category of most deadly and difficult to treat, with mortality rates often exceeding 30-50%. We will elucidate the mechanism of carbapenemase activity of A. baumannii CHDLs and evaluate the evolutionary potential of these class D enzymes to further enhance their catalytic efficiency against carbapenems, rendering this important class of antibiotics obsolete for treatment of infections caused by this bacterial pathogen. Finally, we will design and test inhibitors of class D carbapenemases that would restore clinical utility of carbapenem antibiotic for combating deadly A. baumannii infections.

Public Health Relevance

Class D carbapenemases are bacterial enzymes that destroy the most potent and clinically successful antibiotics, carbapenems. Dissemination of these enzymes in clinical bacterial pathogens impairs our ability to treat serious bacterial infections and results in high mortality rates. Our studies aim at elucidation of mechanisms employed by class D carbapenemases to produce resistance to carbapenems and at development of inhibitors of these enzymes capable of restoring clinical utility of these valuable antibiotics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI114668-04
Application #
9407300
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Xu, Zuoyu
Project Start
2015-08-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Notre Dame
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
824910376
City
Notre Dame
State
IN
Country
United States
Zip Code
46556
Toth, Marta; Smith, Clyde A; Antunes, Nuno T et al. (2017) The role of conserved surface hydrophobic residues in the carbapenemase activity of the class D ?-lactamases. Acta Crystallogr D Struct Biol 73:692-701
Smith, Clyde A; Antunes, Nuno Tiago; Stewart, Nichole K et al. (2015) Structural Basis for Enhancement of Carbapenemase Activity in the OXA-51 Family of Class D ?-Lactamases. ACS Chem Biol 10:1791-6