Department of Biology

Research Area

Microbial Interactions and Pathogenesis

Education

Ph.D., Chemistry Department, Indiana University, Bloomington, IN 1970
Postdoctoral Fellow, University of California, Santa Barbara, 1970-1971

Awards

Fellow of American Academy of Microbiology (2000)

Research Description

My PhD in Biochemistry was directed by Professors Henry Mahler and V. J. Shiner from the Indiana University Chemistry Department, where I studied deuterium isotope effects on the mechanism of action of the zinc-containing alcohol dehydrogenase. Following postdoctoral work, I joined the Squibb Institute for Medical Research in New Jersey where I began studying beta-lactamases, the enzymes in pathogenic bacteria that are the major cause for resistance to penicillins and other beta-lactam antibiotics. My enzymatic studies as a graduate student led to further explorations of the pharmaceutically relevant metalloenzymes, angiotensin-converting enzyme and metallo-beta-lactamases, as I tried to identify novel inhibitors of these enzymes. During my time in the pharmaceutical industry (Squibb 1973-1991; Lederle/Wyeth 1991-1996; Johnson & Johnson, 1997-2009), I was a member of scientific teams that identified and/or developed the antibiotics aztreonam (Azactam), piperacillin-tazobactam (Zosyn), levofloxacin (Levaquin), doripenem (Doribax) and the anti-MRSA cephalosporin ceftobiprole (Zeftera). My laboratory has been responsible for a number of published studies examining the mechanism of action of penicillin-binding proteins (PBPs) and various beta-lactamases that interact with these antibiotics. I have written several sets of review articles that established well-recognized beta-lactamase nomenclature, including the most highly cited article in the ASM journal Antimicrobial Agents & Chemotherapy.

As the head of the Antimicrobial Drug Discovery Research team at J&J, my work involved developing a number of high-throughput screening assays that identified novel inhibitors of bacterial enzyme targets, including the bacterial cell wall synthesizing enzymes MurA and MurF. We worked closely with a medicinal chemistry team to discover new ketolides and novel topoisomerase inhibitors with antibacterial activity against resistant gram-positive pathogens.

Current research: My laboratory is particularly known for characterizing new beta-lactamases and their interactions with various beta-lactam antibiotics. I serve as the co-gatekeeper (with George Jacoby) of the website that monitors beta-lactamase nomenclature. I am currently collaborating with several groups to determine substrate and inhibition profiles and mechanisms of resistance for new b-lactamases from resistant clinical isolates.

Select Publications

Bush, K. and G. A. Jacoby. 2010. An updated functional classification of b-lactamases. Antimicrob. Agents Chemother. 54:969-976

Queenan, A. M., W. Shang, R. Flamm, and K. Bush. 2010. Hydrolysis and inhibition profiles of b-lactamases from molecular classes A to D with doripenem, imipenem and meropenem. Antimicrob. Agents Chemother. 54: 565-569.

Baum, E. Z., S. M. Crespo-Carbone, B. D. Foleno, L. D. Simon, J. Guillemont, M. Macielag and K. Bush. 2009. MurF inhibitors with antibacterial activity: effect on muropeptide levels. Antimicrob. Agents Chemother. 53:3240-3247.

Baum, E. Z., S. M. Crespo-Carbone, B. J. Morrow, T. A. Davies, B. D. Foleno, W. He, A. M. Queenan and K. Bush. 2009. Effect of MexXY overexpression on ceftobiprole susceptibility in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 53:2785-2790.

Amsler, K. M., T. A. Davies, W. Shang, M. R. Jacobs, and K. Bush. 2008. In vitro activity of ceftobiprole against pathogens from two phase 3 complicated skin and skin structure infection clinical trials. Antimicrob. Agents Chemother. 52: 3418-3423.

Queenan, A. M. and K. Bush. 2007. Carbapenemases: the versatile beta-lactamases. Clin. Microbiol. Rev. 20:440-458.

Davies, T.A., M. G. P. Page, W. Shang, M. Kania, and K. Bush. 2007. Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus pneumoniae. Antimicrob. Agents Chemother. 51: 2621-2624.

Tennakoon, M.A., T. C. Henninger, D. Abbanat, B. D. Foleno, J. J. Hilliard, K. Bush, and M. J. Macielag. 2006. Synthesis and antibacterial activity of C6-carbazate ketolides. Bioorg. Med. Chem. Lttr. 16:6231-6235.

Robicsek A., J. Strahilevitz,. G. A. Jacoby, M. Macielag, D. Abbanat, C. H. Park, K. Bush, and D. C.. Hooper. 2006. Fluoroquinolone-modifying enzyme: a new adaptation of a common aminoglycoside acetyltransferase. Nature Med. 12:83-88.

Bush, K., G. A. Jacoby and A. A. Medeiros. 1995. A functional classification scheme for beta-lactamases. Antimicrob. Agents Chemother. 39:1211-1233.

View more publications »