Adjunct Professor
Lecturer, Biotechnology Training Program

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

Fellow of American Academy of Microbiology (2000)

Email Karen

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 at the University of California Santa Barbara, and biochemistry research and teaching at the University of North Carolina and the University of Delaware, I joined the Squibb Institute for Medical Research in New Jersey. At Squibb, and later at Lederle Laboratories, I spent 20 years 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 that time, I was a member of scientific teams that identified and/or developed the antibiotics aztreonam (Azactam) and piperacillin-tazobactam (Zosyn). My laboratory has been responsible for a number of published studies examining the mechanism of action of various beta-lactamases that interact with these antibiotics. I also have written a set of review articles that established well-recognized beta-lactamase nomenclature, including the most highly cited article in the ASM journal Antimicrobial Agents & Chemotherapy.

From 1997 to early 2009 I was the leader of the Microbiology Discovery and Preclinical Anti-infectives research team at Johnson & Johnson Pharmaceutical & Development. During that time our team was responsible for providing research support for the development of levofloxacin (Levaquin), primarily by examining resistance mechanisms in Streptococcus pneumoniae. We also developed 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. My team recently conducted mechanism of action studies (penicillin-binding protein studies) and resistance studies for the investigational drugs doripenem (Doribax) and the anti-MRSA cephalosporin ceftobiprole (Zeftera).  Doribax, an antipseudomonal carbapenem, was approved by the FDA in October 2007 for the treatment of complicated urinary tract infections and complicated intra-abdominal infections. Ceftobiprole is currently under review by the FDA for the treatment of skin infections caused by MRSA.

My laboratory was also known for characterizing new beta-lactamases and their interactions with various beta-lactam antibiotics.  I currently serve as the co-gatekeeper (with George Jacoby) of the website that monitors beta-lactamase nomenclature. Because resistance to all antibiotics will continue to develop with the use of these agents, I anticipate that antibiotic resistance will remain an important focus of my attention. In addition, new approaches to the discovery of novel anti-infectives are also of interest, especially as new targets are validated in pathogenic bacteria.

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., W. Shang, M. Kania, M. G. P. Page, and K. Bush. 2007. Interactions of ceftobiprole with beta-lactamases from molecular classes A to D. Antimicrob. Agents Chemother. 51:3089-3095.

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.

Kao, L. .M., K. Bush, R.. Barnewall, J. Estep, F. W. Thalacker , P. H. Olson, G. L. Drusano, N. Minton, S. Chien, A. Hemeryck, and M. F. Kelley MF. 2006. Pharmacokinetic considerations and efficacy of levofloxacin in an inhalational anthrax (postexposure) rhesus monkey model. Antimicrob. Agents Chemother. 50 3535-3542.

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.