Antistaphylococcal activities of CG400549, a new bacterial enoyl-acyl carrier protein reductase (FabI) inhibitor

<sec><st>Objectives</st> This study was performed to analyse <it>in vitro</it> and <it>in vivo</it> activities of CG400549, a new FabI inhibitor, against clinical isolates of staphylococci. The mode of action of CG400549 and resistance mechanism of <it>Staphylococcus aureus</it> against CG400549 were also investigated by genetic approaches. </sec> <sec><st>Methods</st> <it>In vitro</it> activity of CG400549 was evaluated by the 2-fold agar dilution method as described by the CLSI, and compared with those of oxacillin, erythromycin, ciprofloxacin, sparfloxacin, moxifloxacin, gemifloxacin, vancomycin, linezolid and quinupristin-dalfopristin. <it>In vivo</it> activity of CG400549 was determined against systemic infections in mice. Time–kill curves of CG400549 were analysed at concentrations of 1×, 2× and 4× MIC against <it>S. aureus</it> strains. </sec> <sec><st>Results</st> CG400549 had the lowest MICs among the test compounds against 238 clinical isolates of <it>S</it>. <it>aureus</it> (MIC<inf>90</inf>, 0.25 mg/L) and 51 clinical isolates of coagulase-negative staphylococci (MIC<inf>90</inf>, 1 mg/L). The activity of CG400549 was irrespective of whether the strains were methicillin-susceptible or -resistant. Furthermore, CG400549 was effective by oral or subcutaneous administration against systemic infections in mice. In a time–kill study, CG400549 at concentrations of 1× MIC, 2× MIC and 4× MIC had a bacteriostatic activity during 24 h. A FabI-overexpressing <it>S</it>. <it>aureus</it> strain gave rise to an increase in the MIC of CG400549 compared with the parental strain, while the susceptibilities of the FabI-overexpressing <it>S</it>. <it>aureus</it> strain to the other antibacterial agents such as oxacillin, erythromycin and ciprofloxacin were not affected. This result showed that the mode of action of CG400549 was via inhibition of FabI, which is involved in biosynthesis of fatty acids in bacteria. Study of the resistance mechanism of <it>S</it>. <it>aureus</it> showed that CG400549-resistant mutants of <it>S</it>. <it>aureus</it> had an alteration in FabI at Phe-204 to Leu. </sec> <sec><st>Conclusions</st> CG400549 had potent <it>in vitro</it> and <it>in vivo</it> activity against staphylococci, including methicillin-, ciprofloxacin- and multidrug-resistant staphylococci strains. This compound could be a good candidate for clinical development as a novel anti-MRSA drug. </sec>