When drug inactivation renders the target irrelevant to antibiotic resistance: a case story with beta-lactams

By challenging the efficiency of some of our most useful antimicrobial weap ons, bacterial antibiotic resistance is becoming an increasingly worrying c linical problem. A good antibiotic is expected to exhibit a high affinity f or its target and to reach it rapidly, while escaping chemical modification by inactivating enzymes and elimination by efflux mechanisms. A study of t he behaviour of a beta-lactamase-overproducing mutant of Enterobacter cloac ae in the presence of several penicillins and cephalosporins showed that th e minimum inhibitory concentration (MIC) values for several compounds were practically independent of the sensitivity of the target penicillin binding protein (PBP), even for poor beta-lactamase substrates. This apparent para dox was explained by analysing the equation that relates the antibiotic con centration in the periplasm to that in the external medium. Indeed, under c onditions that are encountered frequently in clinical isolates, the factor characterizing the PBP sensitivity became negligible. The conclusions can b e extended to all antibiotics that are sensitive to enzymatic inactivation and efflux mechanisms and must overcome permeability barriers. It would be a grave mistake to neglect these considerations in the design of future ant ibacterial chemotherapeutic agents.