These results indicate that this TCS senses bacitracin, and also positively regulates the expression of two ABC transporters. Staphylococcus aureus is a major pathogen to humans and often causes

serious problems related to nosocomial infection. This organism, especially methicillin-resistant S. aureus (MRSA), shows multiple resistances to several chemotherapeutic agents, such as β-lactams, quinolones and aminoglycosides (Grundmann et al., 2006; Fischbach & Walsh, 2009). To date, many factors conveying resistance to antibacterial agents have been identified in S. aureus (Ito et al., 2003; Grundmann et al., 2006). Among these factors, recently, some two-component systems (TCSs) have been demonstrated to affect the susceptibility to several Crizotinib nmr antibacterial agents (Sakoulas et al., 2002; Kuroda et al., 2003; Meehl et al., 2007). TCSs have mainly been characterized in terms of the expressions

of virulence factors and adaptation to environmental conditions (Novick, 2003), but some TCSs have been demonstrated to affect the susceptibility to antibacterial agents. VraSR was originally identified as a factor that affects bacterial resistance to vancomycin (Kuroda et al., 2003). VraSR is a positive modulator for the regulation of cell wall biosynthesis, such as for pbpB, sgtB and murZ (Yin et al., 2006). Inhibition of VraSR leads to decreased resistance to cell wall inhibitors, including β-lactams, vancomycin, teicoplanin and fosfomycin (Kuroda et al., 2003; Gardete next et al., 2006). ApsRS/GraRS has been reported Nintedanib in vivo to be involved in vancomycin-intermediate resistance owing to the increased expression of VraFG, an ABC transporter (Meehl et al., 2007; Howden et al., 2008). In addition, ApsRS/GraRS is involved in the susceptibility to cationic antibacterial peptides, such as defensins and LL37, by modulating the bacterial surface charge. Agr, a global regulator for virulence factors, has also been demonstrated to be associated

with vancomycin and daptomycin resistance (Sakoulas et al., 2002; Tsuji et al., 2007). Loss of agr function was linked to the development of vancomycin-intermediate resistance by vancomycin exposure, although the mechanism of this linkage is unclear. Bacitracin is a polypeptide antibiotic produced by Bacillus subtilis and Bacillus licheniformis (Johnson et al., 1945; Azevedo et al., 1993). Bacitracin binds to undecaprenyl pyrophosphate, resulting in inhibition of cell wall biosynthesis (Stone & Strominger, 1971). We previously investigated susceptibility to various antibacterial agents using a group of S. aureus MW2 mutants that are gene inactivated in 15 TCSs, with the exception of one essential TCS (Matsuo et al., 2010).