1. Academic Validation
  2. The MUT056399 inhibitor of FabI is a new antistaphylococcal compound

The MUT056399 inhibitor of FabI is a new antistaphylococcal compound

  • Antimicrob Agents Chemother. 2011 Oct;55(10):4692-7. doi: 10.1128/AAC.01248-10.
S Escaich 1 L Prouvensier M Saccomani L Durant M Oxoby V Gerusz F Moreau V Vongsouthi Kirsty Maher Ian Morrissey C Soulama-Mouze
Affiliations

Affiliation

  • 1 FAB Pharma, 14, avenue de l'Opéra, 75001 Paris, France. sonia.escaich@fabpharma.com
Abstract

MUT056399 is a highly potent new inhibitor of the FabI Enzyme of both Staphylococcus aureus and Escherichia coli. In vitro, MUT056399 was very active against S. aureus strains, including methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), linezolid-resistant, and multidrug-resistant strains, with MIC(90)s between 0.03 and 0.12 μg/ml. MUT056399 was also active against coagulase-negative staphylococci, with MIC(90)s 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 of S. aureus were obtained at a low frequency. All of the resistant clones analyzed were found to contain mutations in the fabI gene. In vivo, MUT056399, administered subcutaneously, protected mice from a lethal systemic Infection induced by MSSA, MRSA, and vancomycin-intermediate S. aureus strains (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.

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