Title: On the track of β-lactam resistance: Studies on the regulation of methicillin- resistance in Staphylococcus aureus
Abstract: Methicillin-resistant Staphylococcus aureus (MRSA) is an important human pathogen, causing a wide range of infections. MRSA has not only developed an intrinsic resistance to all β-lactams, but has also acquired resistance to virtually all classes of antimicrobial agents, leaving clinicians with reduced therapeutic options. β-lactam resistance in MRSA is mediated by two main mechanisms: (i) the β-lactamase (blaZ), which confers resistance to penicillins only, and (ii) mecA gene, conferring cross-resistance to virtually all other β-lactams. Response to β-lactams involves a unique series of proteolytic steps, very uncommon in bacteria, so much so that critical details of this signal transduction mechanism are still deceptive.
In the course of these PhD studies, we have found that the mecA regulatory locus is in fact a three-component system containing, besides regulatory genes mecR1–mecI coding for a sensor-inducer and repressor, the previously unrecognized mecR2 gene, which is co-transcribed together with mecR1–mecI. We demonstrated that mecR2 gene acts as an anti-repressor and is essential for optimal expression of β-lactam resistance in all MRSA strains which carry fully functional mecR1–mecI genes. MecR2 disturbs the binding of the repressor MecI to the mecA promoter, by binding directly to the repressor, fostering its (non-specific) cleavage presumably by native proteases. The crystal structure of MecR2 reveals a three-domain architecture, with an N-terminal DNA-binding-like domain, a C-terminal dimerization domain, and an intermediate scaffold domain, essential for accomplish the MecR2 function. Altogether, these observations point to revision in depth of the current model for the transcriptional control of the mecA gene in MRSA (see Figure 1) (Arêde et al., 2012).
Figure 1 – Revised model for the induction of mecA expression by MecR1-MecI-MecR2.
Arede, P., C. Milheirico, H. de Lencastre, and D.C. Oliveira. (2012). The anti-repressor MecR2 promotes the proteolysis of the mecA repressor and enables optimal expression of beta-lactam resistance in MRSA. PLoS Pathog. 8: e1002816.
PhD Degree: Biology, specialty Molecular Biology; Year of conlusion: 2012
Institution: Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa
Supervision: Duarte C. Oliveira (FCT/UNL) and Hermínia de Lencastre (ITQB/UNL)