Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is an important human pathogen, which is cross-resistant to virtually all β-lactam antibiotics. MRSA strains are defined by the presence of mecA gene. The transcription of mecA can be regulated by a sensor-inducer (MecR1) and a repressor (MecI), involving a unique series of proteolytic steps. The induction of mecA by MecR1 has been described as very inefficient and, as such, it is believed that optimal expression of β-lactam resistance by MRSA requires a non-functional MecR1-MecI system. However, in a recent study, no correlation was found between the presence of functional MecR1-MecI and the level of β-lactam resistance in a representative collection of epidemic MRSA strains. Here, we demonstrate that the mecA regulatory locus consists, in fact, of an unusual three-component arrangement containing, in addition to mecR1-mecI, the up to now unrecognized mecR2 gene coding for an anti-repressor. The MecR2 function is essential for the full induction of mecA expression, compensating for the inefficient induction of mecA by MecR1 and enabling optimal expression of β-lactam resistance in MRSA strains with functional mecR1-mecI regulatory genes. Our data shows that MecR2 interacts directly with MecI, destabilizing its binding to the mecA promoter, which results in the repressor inactivation by proteolytic cleavage, presumably mediated by native cytoplasmatic proteases. These observations point to a revision of the current model for the transcriptional control of mecA and open new avenues for the design of alternative therapeutic strategies for the treatment of MRSA infections. Moreover, these findings also provide important insights into the complex evolutionary pathways of antibiotic resistance and molecular mechanisms of transcriptional regulation in bacteria.
Highlights
Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of infections in hospitals in many countries and has become an important community- and livestock-associated pathogen [1,2,3]
The currently accepted model of mecA regulation involves two main steps: (i) binding of the b-lactam antibiotic to the extracellular sensor domain of MecR1 leads to the autocatalytic cleavage of the sensorinducer and activation of the cytoplasmatic inducer domain, which appears to be a prometalloprotease; (ii) the activated inducer domain of MecR1 either directly cleaves the promoterbound MecI dimers or promotes the repressor cleavage, which disables the ability of the repressor protein to dimerize and bind to Methicillin-resistance Staphylococcus aureus (MRSA) is an important human pathogen, causing a wide range of infections
Concluding remarks This study demonstrates that the central element of methicillinresistance in S. aureus, the mecA gene, can be regulated by a threecomponent system consisting of a transcriptional repressor, a sensor-inducer and an anti-repressor, a very unusual arrangement for the transcriptional control of genes in bacteria
Summary
Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of infections in hospitals in many countries and has become an important community- and livestock-associated pathogen [1,2,3]. The mecA transcription can be controlled by the divergent mecR1-mecI regulatory genes, coding for a sensor-inducer and a repressor, respectively [10]. This genetic organization of the mecA locus is similar to that of the b-lactamase, which contains the structural gene blaZ and the homologous blaR1-blaI regulatory genes. The currently accepted model of mecA regulation involves two main steps: (i) binding of the b-lactam antibiotic to the extracellular sensor domain of MecR1 leads to the autocatalytic cleavage of the sensorinducer and activation of the cytoplasmatic inducer domain, which appears to be a prometalloprotease; (ii) the activated inducer domain of MecR1 either directly cleaves the promoterbound MecI dimers or promotes the repressor cleavage, which disables the ability of the repressor protein to dimerize and bind to
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