ABSTRACT
A series of 3α-amino-5α-cholestane and 3α,7α-diamino-5α-cholestane derivatives containing imidazole and pyridine rings were synthesized by simple and effective reductive amination, and their in vitro activities against a range of Gram-positive and Gram-negative strains were evaluated. Most of the compound exhibited enhanced activity against MRSA pathogen. 3α,7α-Di(pyridylmethyl)amino-5α-cholestane 10 showed the highest potency in these series toward the Gram-positive bacteria, Staphylococcus epidermidis 887E, with the lowest MIC value of 1 µg/mL.
Subject(s)
Anti-Infective Agents/chemical synthesis , Cholestanes/chemistry , Imidazoles/chemistry , Pyridines/chemistry , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Staphylococcus epidermidis/drug effectsABSTRACT
LCB01-0062, a novel oxazolidinone, has potent antibacterial activity against clinical isolates of Gram-positive bacteria. The in vitro activity of LCB01-0062 was compared with that of linezolid, oxacillin, erythromycin, ciprofloxacin, vancomycin and quinupristin/dalfopristin. Among the tested agents, LCB01-0062 showed the most potent antibacterial activity against meticillin-resistant Staphylococcus aureus, meticillin-resistant coagulase-negative staphylococci and vancomycin-resistant enterococci. LCB01-0062 was 4-8-fold more active than linezolid, the first oxazolidinone drug, against Gram-positive bacteria. The time-kill curves of LCB01-0062 were analysed at concentrations of 0.5×, 1×, 2×, 4× and 8× the minimum inhibitory concentration against S. aureus strains. LCB01-0062 showed bacteriostatic activity during 24 h. LCB01-0062 was also more effective than linezolid against S. aureus in a systemic mouse model of infection.
Subject(s)
Anti-Bacterial Agents/pharmacology , Gram-Positive Bacteria/drug effects , Oxazolidinones/pharmacology , Colony Count, Microbial , Gram-Negative Bacteria/drug effects , Microbial Sensitivity Tests , Microbial Viability/drug effects , Molecular Structure , Time FactorsABSTRACT
LCB01-0371 is a new oxazolidinone with cyclic amidrazone. In vitro activity of LCB01-0371 against 624 clinical isolates was evaluated and compared with those of linezolid, vancomycin, and other antibiotics. LCB01-0371 showed good activity against Gram-positive pathogens. In vivo activity of LCB01-0371 against systemic infections in mice was also evaluated. LCB01-0371 was more active than linezolid against these systemic infections. LCB01-0371 showed bacteriostatic activity against Staphylococcus aureus.
Subject(s)
Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Oxazolidinones/pharmacology , Acetamides/pharmacology , Acetamides/therapeutic use , Animals , Bacterial Infections/drug therapy , Bacterial Infections/microbiology , Gram-Positive Bacteria/drug effects , Linezolid , Male , Mice , Mice, Inbred ICR , Oxazolidinones/therapeutic use , Staphylococcus aureus/drug effects , Vancomycin/pharmacology , Vancomycin/therapeutic useABSTRACT
DW286 is a novel broad-spectrum fluoroquinolone with excellent antipneumococcal activity. The in vitro activity of DW286 was evaluated against quinolone-susceptible and -resistant Streptococcus pneumoniae and was compared with the activities of reference compounds. Among the tested agents, DW286 showed the most potent antibacterial activity against 94 quinolone-susceptible strains [minimum inhibitory concentration (MIC) 0.008-0.03 mg/L]. Against 23 quinolone-resistant S. pneumoniae with known resistance mechanisms, DW286 also had the lowest MICs of all the tested quinolones [MIC at which 90% of isolates were inhibited (MIC(90))=0.5mg/L], followed by ciprofloxacin, sparfloxacin, moxifloxacin and gemifloxacin. The in vivo activity of DW286 against penicillin-susceptible and -resistant S. pneumoniae was more effective than that of gemifloxacin.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacology , Fluoroquinolones/administration & dosage , Fluoroquinolones/pharmacology , Pneumococcal Infections/drug therapy , Streptococcus pneumoniae/drug effects , Animals , Disease Models, Animal , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , Sepsis/drug therapy , Survival AnalysisSubject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , DNA Topoisomerase IV/antagonists & inhibitors , Streptococcus pneumoniae/drug effects , Streptococcus pneumoniae/enzymology , Topoisomerase II Inhibitors , Amino Acid Substitution/genetics , Bacterial Proteins/genetics , DNA Gyrase/genetics , DNA Topoisomerase IV/genetics , Humans , Microbial Sensitivity Tests , Mutation, MissenseABSTRACT
CG400462, a novel FabI inhibitor, has a potent antibacterial activity against staphylococci. The minimal inhibitory concentration at which 90% of bacterial strains tested were inhibited (MIC(90)) of CG400462 was 0.5 microg/mL against 238 strains of Staphylococcus aureus and 1.0 microg/mL against 51 strains of coagulase-negative staphylococci, irrespective of whether the strains were methicillin-susceptible or -resistant. CG400462 was also effective by subcutaneous administration against systemic infections in mice. In time-kill studies, CG400462 at concentrations of 1x, 2x and 4x MIC had a bacteriostatic activity over 24h. Genetic approaches have confirmed that the mode of action of CG400462 is via inhibition of FabI, which is involved in the biosynthesis of fatty acids in bacteria. Study of the resistance mechanism of S. aureus showed that CG400462-resistant mutants had an alteration in FabI of Met99-->Thr or Tyr147-->His.
Subject(s)
Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Staphylococcus/drug effects , Amino Acid Substitution/genetics , Animals , Drug Resistance, Bacterial/genetics , Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/genetics , Male , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , Staphylococcal Infections/drug therapyABSTRACT
OBJECTIVES: 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.
