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.
