department of pharmacology

Robert Bonomo, M.D.

bonomo

Professor of Medicine, Pharmacology, and Molecular Biology and Microbiology

Geriatric Care Center 111C (W)
12200 Fairhill Rd.
Cleveland, OH 44120

Research Service
Veterans Affairs Medical Center
10701 East Blvd.
Cleveland. OH 44106

Phone: (216) 791-3800 x4399
Fax: (216) 229-8509
E-mail: rab14@case.edu

Research

Bacterial resistance to beta-lactams is threatening the most potent antibiotics we have. The research interests in our laboratory involve understanding the structure function relationships of the class A beta-lactamase, SHV-1. This chromosomal and plasmid encoded beta-lactamase is usually found in Klebsiella pneumonia and confers high level resistance to third generation cephalosporins (cefotaxime, ceftazidime, and aztreonam). This resistance can render ineffective the most frequently used drugs to treat serious nosocomial infections. Our goals are to understand what amino acid substitutions permit evolution of novel substrate profiles and what factors control expression of these periplasmic enzymes. By using site directed mutagenesis and immunological tools to quantify expression, we are able to draw conclusions as to why these highly resistant variants may have arisen in nature. We are also interested in quantifying beta-lactamase expression in organisms harboring Class C beta-lactamases. We have developed antibodies able to detect the presence of this class of enzymes in clinical strains, thereby facilitating molecular epidemiological investigations.

SELECTED REFERENCES:

Lin, S., Thomas, M., Bonomo, R.A.. 1999. OHIO-1 b-lactamase mutants: The Arg 244Ser mutation and resistance to b-lactams and b-lactamase inhibitors, Biochem Biophys Acta, 1432 15: 125-136.

Kuzin, A., Nukaga, M., Nukaga, Y., Hujer, A.M., Bonomo, R.A., Knox, J.R. 1999. Structure of SHV-1 b-lactamase, Biochemistry, 38: 5720-5727.

Tzouvelekis, L.S., Bonomo, R.A. 1999. SHV-type b-lactamases. Current Pharmaceutical Design 5, 847-864.

Rice L.B., Carias, L.L., Hujer, A.M., Bonafede, M., Hutton, R., Bonomo, R.A. 2000 High-level expression of chromosomally encoded SHV-1 and an outer membrane protein change conferring Klebsiella pneumoniae. Antimicrob Agents Chemother 44:362-367.