The Anti-Repressor MecR2 Promotes the Proteolysis of the mecA Repressor and Enables Optimal Expression of β-lactam Resistance in MRSA

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Arêde, Pedro ; Milheiriço, Catarina ; de Lencastre, Hermínia ; C. Oliveira, Duarte (2012)
  • Publisher: Figshare
  • Related identifiers: doi: 10.1371/journal.ppat.1002816
  • Subject: Molecular Biology | mrsa | mecr2 | repressor | optimal | Microbiology | anti-repressor | Cell Biology | Genetics | Cancer | promotes | proteolysis | enables
    mesheuropmc: bacterial infections and mycoses | biochemical phenomena, metabolism, and nutrition

<div><p>Methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) is an important human pathogen, which is cross-resistant to virtually all β-lactam antibiotics. MRSA strains are defined by the presence of <em>mecA</em> gene. The transcription of <em>mecA</em> can be regulated by a sensor-inducer (MecR1) and a repressor (MecI), involving a unique series of proteolytic steps. The induction of <em>mecA</em> 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 <em>mecA</em> regulatory locus consists, in fact, of an unusual three-component arrangement containing, in addition to <em>mecR1-mecI</em>, the up to now unrecognized <em>mecR2</em> gene coding for an anti-repressor. The MecR2 function is essential for the full induction of <em>mecA</em> expression, compensating for the inefficient induction of <em>mecA</em> by MecR1 and enabling optimal expression of β-lactam resistance in MRSA strains with functional <em>mecR1-mecI</em> regulatory genes. Our data shows that MecR2 interacts directly with MecI, destabilizing its binding to the <em>mecA</em> 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 <em>mecA</em> 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.</p> </div>
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