In S. aureus, methicillin resistance is conferred by an acquired, β-lactam-insensitive penicillin-binding protein (PBP), PBP2a [1–4]. PBP2a is encoded by mecA, which is divergently transcribed from its cognate regulators, mecR1 (sensor/signal transducer) and mecI (repressor).

If mecR1-mecI are absent or truncated, transcriptional control of mecA is taken over by the structurally similar blaZ (penicillinase) regulatory elements blaR1/blaI, if present. In the absence of both regulatory loci, mecA is constitutively transcribed [5, 6]. In the presence of β-lactams, the transmembrane sensor/signal transducers BlaR1/MecR1, undergo a conformational change, followed by autoproteolytic cleavage of the n-terminal cytoplasmic domain, leading to the activation of the cytoplasmic peptidase Tariquidar and subsequent dissociation of the repressor

due to proteolytic degradation [7–9]. However, the signal transduction cascade of this regulatory system has still not been completely elucidated. CX-6258 mw Oxacillin resistance levels conferred by mecA are strain specific and can vary greatly, with oxacillin minimal inhibitory concentrations (MICs) of different strains ranging from phenotypically susceptible levels, as low as 1 μg/ml up to extremely high values of > 500 μg/ml. Methicillin resistance is also generally expressed heterogeneously. Heterogeneously

resistant MRSA, when exposed to β-lactam antibiotics, segregate highly resistant subpopulations, which are much more resistant than the majority of the cells [10]. The frequency Linifanib (ABT-869) of highly resistant subclones generated is often well above the spontaneous mutation frequency, and once selected high level resistance often remains stable, even in the absence of selective pressure. There is currently no satisfactory genetic model which explains how these higher resistance levels are triggered or selected and exactly what factors are functionally responsible for the increased resistance in clinical isolates. Methicillin resistance levels are known to not directly correlate with mecA transcription or levels of PBP2a mTOR signaling pathway produced [11, 12]. However, resistance levels can be manipulated by environmental conditions, such as temperature, pH, osmolarity, and medium composition [13, 14]. It has been shown experimentally, that in addition to mecA, methicillin resistance depends on the correct interplay of a multitude of genomic factors, termed fem/aux factors, including genes involved in peptidoglycan precursor formation, composition and turnover; teichoic acid synthesis; and genes of unknown or poorly characterised functions [15–18].