Abstract
To resist to β-lactam antibiotics Eubacteria either constitutively synthesize a β-lactamase or a low affinity penicillin-binding protein target, or induce its synthesis in response to the presence of antibiotic outside the cell. In Bacillus licheniformis and Staphylococcus aureus, a membrane-bound penicillin receptor (BlaR/MecR) detects the presence of β-lactam and launches a cytoplasmic signal leading to the inactivation of BlaI/MecI repressor, and the synthesis of a β-lactamase or a low affinity target. We identified a dipeptide, resulting from the peptidoglycan turnover and present in bacterial cytoplasm, which is able to directly bind to the BlaI/MecI repressor and to destabilize the BlaI/MecI-DNA complex. We propose a general model, in which the acylation of BlaR/MecR receptor and the cellular stress induced by the antibiotic, are both necessary to generate a cell wall-derived coactivator responsible for the expression of an inducible β-lactam-resistance factor. The new model proposed confirms and emphasizes the role of peptidoglycan degradation fragments in bacterial cell regulation.
Highlights
The introduction of penicillin, a b-lactam antibiotic, to treat bacterial infection, has drastically reduced the cases of human morbidity and mortality
Blactam antibiotic resistance can be obtained by one of the three following mechanisms: (i) inactivation of the b-lactam molecule by a specific hydrolase, the b-lactamase [1,2,3]; (ii) alteration of the blactam targets, the membrane-bound D,D-transpeptidases, that renders them insensitive to the action of the antibiotic [4]. These enzymes, which catalyze the final step of the bacterial cell wall biosynthesis, are inactivated by penicillin through acylation of their active serine by the antibiotic
We identified that a dipeptide issued from the bacterial cell wall is able to inactivate the BlaI repressor
Summary
The introduction of penicillin, a b-lactam antibiotic, to treat bacterial infection, has drastically reduced the cases of human morbidity and mortality. A tight control of these bacterial pathogens has never been achieved and the use of blactam antibiotics appears to be linked to the selection and the spread of b-lactam resistant clinical isolates In these strains, blactam antibiotic resistance can be obtained by one of the three following mechanisms: (i) inactivation of the b-lactam molecule by a specific hydrolase, the b-lactamase [1,2,3]; (ii) alteration of the blactam targets, the membrane-bound D,D-transpeptidases, that renders them insensitive to the action of the antibiotic [4]. This mechanism of resistance is only found in Gram-negative bacteria and can be due to the alteration of porins and/or the presence of an efflux pump [6,7,8]
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