Evaluation of penicillin-based inhibitors of the class A and B β-lactamases from Bacillus anthracis

Bacillus anthracis contains a class A (Bla1) and class B (Bla2) 0-lactamase, which confer resistance to beta-lactam antibiotics when expressed in Escherichia coli. In an effort to find new P-lactamase inhibitors, several penicillin derivatives have been evaluated including experimental compounds incorporating a 6-mercaptomethyl group or a 6-pyridylmethylidene group, along with clavulanate and tazobactam, as inhibitors against Bla1 and Bla2. The 6-mercaptomethyl-substituted penicillins showed much greater activity against the zinc-containing Bla2 than Bla1. The compound that incorporated a 6-pyridylmethylidene substituent and a catecholic substituent at the 2' position was the most effective inhibitor of Bla1 with K-i = 0.057 muM. Inhibitors containing iron-chelating functional groups have previously been shown to work in combination with antibiotics to inhibit growth of antibiotic-resistant bacteria expressing P-lactamase. The development of similar compounds, incorporating these types of substituents, may help overcome resistance to currently used antibiotics. (C) 2003 Elsevier Inc. All rights reserved.