How β-Lactamases Have Driven Pharmaceutical Drug Discovery

Abstract

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.