Mechanisms of beta-lactam antibiotics resistance will be investigated. New methodologies in the area combining quantum mechanics and molecular mechanics calculations, free energy perturbations, and continuum electrostatics models will be applied to examine the hydrolytic activity against beta-lactam antibiotics displayed by the bacterial defensive enzymes which render bacterial resistance-TEM-1 from E. coli and E. cloacae P99 beta-lactamases, which are common in clinical pathogens. The mechanism of catalysis will be first studied on simple models of methanol-mediated hydrolysis of small beta-lactam molecules in the gas phase and in the solution followed by the modeling for the methanol- mediated hydrolysis of benzylpenicillin-a typical beta-lactam antibiotic. Titration curves will be calculated for the representative beta-lactamases in order to elucidate mechanisms of activation of the critical active-site residues in these enzymes. Ultimately, the entire mechanism of the beta-lactam antibiotic hydrolysis by beta-lactamases will be studied. The detailed knowledge gained from the science disclosed in this proposal should ultimately be a driving force in designing novel potent antimicrobials that overcome the problem of bacterial resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AI009998-01
Application #
2517162
Study Section
Special Emphasis Panel (ZRG3-BBCA (03))
Project Start
1998-06-30
Project End
Budget Start
1998-01-01
Budget End
1998-12-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143