How β-Lactamases Have Driven Pharmaceutical Drug Discovery

From Mechanistic Knowledge to Clinical Circumvention
  • Karen Bush
  • Shahriar Mobashery
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 456)


Although antibiotic resistance has only recently become a recognized topic for the popular press, resistance has been the major stimulus for the pharmaceutical development of novel β-lactam antibiotics. Benzylpenicillin (Penicillin G), the first member of this important class of antibacterial agents, was initially used to counteract Gram-positive infections, particularly those caused by Streptococcus pneumoniae, the scourge of hospitals in the 1940s. Before penicillins found widespread clinical utility, it was discovered that certain bacterial enzymes, the β-lactamases, had the ability to hydrolyze the lactam ring of these antibiotics and render them ineffective as antibacterial agents (Abraham and Chain, 1940; Kirby, 1944). When resistance to penicillin was soon selected rapidly by β-lactamase-producing bacteria, it became obvious that the hydrolytic β-lactamases could potentially destroy the utility of this potent class of antibiotics. The pharmaceutical industry has proceeded to identify novel β-lactams over the past 40 years in an attempt to keep ahead of the continuous evolution of new β-lactamases with altered hydrolytic properties. Two approaches were undertaken: development of agents stable to hydrolysis by the major β-lactamases, and identification of potent inhibitors for these enzymes. The topics germane to these strategies will be addressed in this manuscript.


Clavulanic Acid Hydrolytic Water C1avulanic Acid Transpeptidation Reaction Renal Dipeptidase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Karen Bush
    • 1
  • Shahriar Mobashery
    • 2
  1. 1.Drug DiscoveryR. W. Johnson Pharmaceutical Research InstituteRaritanUSA
  2. 2.Department of ChemistryWayne State UniversityDetroitUSA

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