Redefining the Role of the β-Lactamase Locus in Methicillin-Resistant Staphylococcus aureus: β-Lactamase Regulators Disrupt the MecI-Mediated Strong Repression onmecAand Optimize the Phenotypic Expression of Resistance in Strains with ConstitutivemecAExpression

Abstract

ABSTRACTIn response to β-lactam chemotherapy,Staphylococcus aureushas acquired two resistance determinants:blaZ, coding for β-lactamase, which confers resistance to penicillins only, andmecA, coding for an extra cell wall cross-linking enzyme with reduced affinity for virtually all other β-lactams. The transcriptional control of both resistance determinants is regulated by homologous repressors (BlaI and MecI, respectively) and sensor inducers (BlaR1 and MecR1, respectively). There is a cross-talk between the two regulatory systems, and it has been demonstrated thatblaregulators stabilize themecAacquisition. In a recent study, we have unexpectedly observed that in most MRSA strains, there was no significant change in the resistance phenotype upon the overexpression intransof a MecI repressor, whereas in those few strains negative for theblalocus, there was a massive decrease of resistance (D. C. Oliveira and H. de Lencastre, PLoS One 6:e23287, 2011). Here, we demonstrate that, contrary to what is currently accepted, theblaregulatory system efficiently disrupts the strong MecI-mediated repression onmecA, enabling the optimal expression of resistance. This effect appears to be due to the formation of MecI::BlaI heterodimers that might bind less efficiently to themecApromoter and become nonfunctional due to the proteolytic inactivation of the BlaI monomer. In addition, we have also observed that the presence ofblaregulators may enhance dramatically the expression of β-lactam resistance in MRSA strains with constitutivemecAexpression, compensating for the fitness cost imposed by the large β-lactamase plasmid. These observations point to important unrecognized roles of theblalocus for the expression of the methicillin-resistantS. aureus(MRSA) phenotype.