title: The MUT056399 inhibitor of FabI is a new antistaphylococcal compound.
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.
authors.affiliation: FAB Pharma, 14, avenue de l'Opéra, 75001 Paris, France. sonia.escaich@fabpharma.com
authors.forename: S
authors.initials: S
authors.lastname: Escaich
authors.forename: L
authors.initials: L
authors.lastname: Prouvensier
authors.forename: M
authors.initials: M
authors.lastname: Saccomani
authors.forename: L
authors.initials: L
authors.lastname: Durant
authors.forename: M
authors.initials: M
authors.lastname: Oxoby
authors.forename: V
authors.initials: V
authors.lastname: Gerusz
authors.forename: F
authors.initials: F
authors.lastname: Moreau
authors.forename: V
authors.initials: V
authors.lastname: Vongsouthi
authors.forename: Kirsty
authors.initials: K
authors.lastname: Maher
authors.forename: Ian
authors.initials: I
authors.lastname: Morrissey
authors.forename: C
authors.initials: C
authors.lastname: Soulama-Mouze
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D024901:Drug Resistance, Multiple, Bacterial; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D054889:Fatty Acid Synthase, Type II / Q000037:antagonists & inhibitors / Q000235:genetics; D005260:Female; D000069349:Linezolid; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009154:Mutation; D023303:Oxazolidinones / Q000494:pharmacology; D010647:Phenyl Ethers / Q000494:pharmacology* / Q000627:therapeutic use; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects*; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D001549:Benzamides; D029968:Escherichia coli Proteins; C570440:MUT056399; D023303:Oxazolidinones; D010647:Phenyl Ethers; D014640:Vancomycin; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); C493924:fabI protein, E coli; D054889:Fatty Acid Synthase, Type II; D000069349:Linezolid