Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is intrinsically cross-resistant to virtually all β-lactam antibiotics. The central determinant for the MRSA phenotype is the mecA gene, whose transcriptional control may be mediated by a repressor (mecI) and a sensor/inducer (mecR1). The mecI-mecR1-mediated induction of mecA takes several hours rendering the strains phenotypically susceptible in spite of the presence of the resistance gene. Therefore, it has been proposed that the full resistance to β-lactams observed in many contemporary clinical MRSA strains requires a non-functional mecI-mecR1 regulatory system. The mecA gene is embedded in a large chromosomal cassette (the SCCmec element) for which several structural types have been described. Some epidemic MRSA clones, typically expressing full β-lactam resistance, carry SCCmec elements that contain an intact mecI-mecR1 locus (e.g. SCCmec types II and III). We have addressed this apparent contradiction by first sequencing the mecI coding region and mecA promoter sequences in a collection of prototype MRSA strains characterized by different SCCmec types. A conserved non-sense mutation within mecI was detected in all SCCmec type III strains tested, presumably responsible for a non-functional truncated MecI protein and, therefore, explaining the full resistance phenotype. In SCCmec type II strains no conserved mutations were found. We next transformed a collection of prototype MRSA epidemic strains with a recombinant plasmid overexpressing a wild-type copy of mecI. Surprisingly, for the great majority of the strains no significant alterations in the phenotypic expression of β-lactam resistance could be detected. These findings were confirmed and further explored, challenging the currently accepted mechanism of mecA transcriptional control. Our observations suggest the existence of yet unidentified additional determinants involved in the transcriptional control of mecA gene and point to a revision of the mecA regulatory mechanism in contemporary MRSA strains.
Highlights
Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of nosocomial infections worldwide and has emerged as a community-associated pathogen [1]
Except for one mutation in the position 25 detected in a ST5, SCCmec type II strain, no point mutations were found in the promoter sequence of the mecA gene, when compared to the published sequence for the prototype strain N315 [5]
Due to the extremely slow induction of mecA expression mediated by mecImecR1 regulators, it is believed that the high-level b-lactam resistance characteristic of many contemporary clinical MRSA strains requires a non-functional mecI-mecR1 regulatory locus [5,9]
Summary
Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of nosocomial infections worldwide and has emerged as a community-associated pathogen [1]. The mecI-mecR1 mediated induction of mecA expression is so slow that, in clinical terms, fully functional mecI and mecR1 genes render the cell phenotypically susceptible in spite of the presence of mecA – the so-called ‘‘pre-MRSA’’ phenotype [5,9]. In agreement with this observation, the in vitro deletion of the mecI gene has been shown to increase the resistance levels to blactams in staphylococci [5,9,10]
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