We have previously observed that thioridazine reduces the oxacillin-dependent induction of the resistance genes mecA and blaZ (Klitgaard et al., 2008). Besides the acquisition of mecA, the resistance level of MRSA strains is influenced by the expression

levels of several housekeeping genes that are either directly or indirectly involved in cell wall biosynthesis and cell wall turnover (Fig. 1). These include the bifunctional native PBP2 of which the transglycosylase domain was shown to be necessary to retain high-level resistance in the MRSA strain COL (Pinho et al., 2001) and the femAB operon, which encodes two peptidyl transferases that are necessary for the formation of pentaglycine bridges and, hence, the cross-linking of peptidoglycan layers (Stranden et al., 1997). Additionally, the two-component system VraSR is an important factor in the tolerance of S. aureus to a broad range of antibiotics targeting the cell wall click here (Kuroda et al., 2003). Upon perturbation of cell wall synthesis, VraSR induces the transcription of BIBF 1120 ic50 a number of genes including murZ (a redundant MurA isozyme) (Blake et al., 2009), pbpB (PBP2), sgtB (a soluble transglycosylase), and fmtA (an accessory PBP with low affinity to β-lactams)(Utaida et al., 2003; McAleese et al., 2006; Fan et al., 2007), all of which

are involved in murein monomer synthesis or peptidoglycan polymerization. The involvement of another native PBP, PBP4 (encoded by the pbpD gene), in β-lactam resistance is not as certain and might be strain specific. PBP4, which possesses transpeptidase, carboxypeptidase, and β-lactamase activity (Kozarich & Strominger, 1978), is necessary to achieve a highly cross-linked cell wall (Leski & Tomasz, 2005) and was shown to play a prominent role in the β-lactam resistance of community-acquired MRSA (Memmi et al., 2008). However, in the highly resistant MRSA strain COL, PBP4 seems to be largely dispensable (Katayama et al., 2003; Memmi et al., 2008). The pbpD gene shares an overlapping promoter region with the divergently transcribed Quisqualic acid abcA gene, encoding an ATP-dependent

transporter of the ABC superfamily (Domanski et al., 1997). The abcA gene product functions as an efflux pump (Truong-Bolduc & Hooper, 2007) and its expression is controlled by the global regulatory agr system (Schrader-Fischer & Berger-Bachi, 2001). AbcA is involved in control of autolytic activities, offering a protective role against β-lactams (Schrader-Fischer & Berger-Bachi, 2001). Concordantly, overproduction of AbcA was shown to result in increased β-lactam resistance (Truong-Bolduc & Hooper, 2007). The agr quorum-sensing system is induced at high cell densities in response to the extracellular cell-density-dependent accumulation of autoinducer. The agr locus regulates the production of virulence factors by repressing expression of cell surface associated factors and activating expression of secreted toxins and enzymes (Vandenesch et al., 1991; Saravia-Otten et al., 1997; Ziebandt et al.