Reference : When Drug Inactivation Renders the Target Irrelevant to Antibiotic Resistance: A Case...
Scientific journals : Article
Life sciences : Microbiology
Life sciences : Biochemistry, biophysics & molecular biology
When Drug Inactivation Renders the Target Irrelevant to Antibiotic Resistance: A Case Story with Beta-Lactams
Lakaye, Bernard mailto [Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biochimie et physiologie humaine et pathologique >]
Dubus, Alice mailto [Université de Liège - ULiège > Département de chimie (sciences) > Département de chimie (sciences) >]
Lepage, Sylvie [Université de Liège - ULiège > Département des sciences cliniques > Département des sciences cliniques >]
Groslambert, S. [> > > >]
Frère, Jean-Marie mailto [Université de Liège - ULiège > Département des sciences de la vie > Département des sciences de la vie >]
Molecular Microbiology
Yes (verified by ORBi)
[en] By challenging the efficiency of some of our most useful antimicrobial weapons, bacterial antibiotic resistance is becoming an increasingly worrying clinical problem. A good antibiotic is expected to exhibit a high affinity for its target and to reach it rapidly, while escaping chemical modification by inactivating enzymes and elimination by efflux mechanisms. A study of the behaviour of a beta-lactamase-overproducing mutant of Enterobacter cloacae in the presence of several penicillins and cephalosporins showed that the 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 paradox was explained by analysing the equation that relates the antibiotic concentration in the periplasm to that in the external medium. Indeed, under conditions that are encountered frequently in clinical isolates, the factor characterizing the PBP sensitivity became negligible. The conclusions can be 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 antibacterial chemotherapeutic agents.

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1999, Mol.MicrobiolPublisher postprint408.15 kBRequest copy

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