Overcoming enzymatic resistance in bacteria: impact on future therapy

Abstract

Resistance of bacteria to antibiotics often involves inactivating enzymes. One approach developed to overcome this mechanism of resistance consists of combining an efficient but possibly unstable antibiotic with a powerful inhibitor of the inactivating enzyme. Attempts have been made with different antibiotics but significant success has only been obtained with the beta-lactams, clavulanic acid and sulbactam being the only compounds currently being used clinically. Sulbactam, a time-dependent irreversible inhibitor of plasmid-mediated penicillinases and of chromosomally mediated penicillinases and cephalosporinases, potentiates the antibacterial activity of beta-lactams but only exhibits a moderate antibacterial activity, which is related to its affinity for the lethal targets of the beta-lactams--the penicillin-binding proteins. In bacterial strains that produce either low amounts of beta-lactamase, or none at all, a synergistic effect can be observed when sulbactam is associated with a beta-lactam antibiotic that has a complementary affinity for the target sites.