Antistaphylococcal activities of CG400549, a new bacterial enoyl-acyl carrier protein reductase (FabI) inhibitor.
OBJECTIVE
This study was performed to analyse in vitro and in vivo activities of CG400549, a new FabI inhibitor, against clinical isolates of staphylococci. The mode of action of CG400549 and resistance mechanism of Staphylococcus aureus against CG400549 were also investigated by genetic approaches.


METHODS
In vitro activity of CG400549 was evaluated by the 2-fold agar sdilution method as described by the CLSI, and compared with those of oxacillin, erythromycin, ciprofloxacin, sparfloxacin, moxifloxacin, gemifloxacin, vancomycin, linezolid and quinupristin-dalfopristin. In vivo activity of CG400549 was determined against systemic infections in mice. Time-kill curves of CG400549 were analysed at concentrations of 1 x , 2 x and 4 x MIC against S. aureus strains.


RESULTS
CG400549 had the lowest MICs among the test compounds against 238 clinical isolates of S. aureus (MIC90, 0.25 mg/L) and 51 clinical isolates of coagulase-negative staphylococci (MIC90, 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 x MIC, 2 x MIC and 4 x MIC had a bacteriostatic activity during 24 h. A FabI-overexpressing S. aureus strain gave rise to an increase in the MIC of CG400549 compared with the parental strain, while the susceptibilities of the FabI-overexpressing S. aureus 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 S. aureus showed that CG400549-resistant mutants of S. aureus had an alteration in FabI at Phe-204 to Leu.


CONCLUSIONS
CG400549 had potent in vitro and in vivo 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.
Park
Hee Soo
HS
School of Life and Food Sciences, Handong Global University, Pohang 791-708, South Korea.
Yoon
Yu Min
YM
Jung
Sung Ji
SJ
Kim
Cheol Min
CM
Kim
Jeong Mi
JM
Kwak
Jin-Hwan
JH
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001550:Benzamidines / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D008826:Microbial Sensitivity Tests; D009499:Neutral Red; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013844:Thiazoles
D000900:Anti-Bacterial Agents; D001550:Benzamidines; D006146:Guanidines; D013778:Tetrazolium Salts; D013844:Thiazoles; C005748:synthalin A; D009499:Neutral Red; C018961:hexamidine; C022616:thiazolyl blue