The MUT056399 Inhibitor of FabI Is a New Antistaphylococcal Compound

Abstract

ABSTRACTMUT056399 is a highly potent new inhibitor of the FabI enzyme of bothStaphylococcus aureusandEscherichia coli. In vitro, MUT056399 was very active againstS. aureusstrains, including methicillin-susceptibleS. aureus(MSSA), methicillin-resistantS. aureus(MRSA), linezolid-resistant, and multidrug-resistant strains, with MIC90s between 0.03 and 0.12 μg/ml. MUT056399 was also active against coagulase-negative staphylococci, with MIC90s between 0.12 and 4 μg/ml. The antibacterial spectrum is consistent with specific FabI inhibition with no activity against bacteria using FabK but activity against FabI-containing Gram-negative bacilli.In vitro, resistant clones ofS. aureuswere obtained at a low frequency. All of the resistant clones analyzed were found to contain mutations in thefabIgene.In vivo, MUT056399, administered subcutaneously, protected mice from a lethal systemic infection induced by MSSA, MRSA, and vancomycin-intermediateS. aureusstrains (50% effective doses ranging from 19.3 mg/kg/day to 49.6 mg/kg/day). In the nonneutropenic murine thigh infection model, the same treatment with MUT056399 reduced the bacterial multiplication of MSSA and MRSA in the thighs of immunocompetent mice. These properties support MUT056399 as a very promising candidate for a novel drug to treat severe staphylococcal infections.