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 g/ml. MUT056399 was also active against coagulase-negative staphylococci, with MIC 90 s between 0.12 and 4 g/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.

Challenges of Antibacterial Discovery

“…4H), an aryloxyphenol inhibitor based on triclosan, is highly active against staphylococci and has activity only against organisms containing solely FabI (92). Resistance was found at 10 Ϫ8 at 4 times the MIC (106).…”

“…In vivo models were used to show the efficacy of the FabI inhibitors described above. AFN-1252 is active in a murine subcutaneous abscess model (384), the similar GSK inhibitors are active in a rat groin abscess model (294), and MUT37307 is active in methicillin-susceptible S. aureus (MSSA) and MRSA septicemia and thigh abscess in a murine model (106). While not all infections involve growth in the presence of serum and long-chain fatty acids may not be sufficient for supplementation at some infection sites, it should be noted that the free linoleic and oleic acid concentrations in staphylococcal abscesses are 1.2 mg/ml (4.2 mM) and 0.9 mg/ml (3.2 mM), respectively (calculated from data in reference 332), similar to those in whole serum (46).…”

Investigational Antimicrobial Agents of 2013

“…It was shown to be specific for inhibition of FabI in S. aureus and E. coli but did not inhibit the FabK homologs from other Gram-positive bacteria. While the frequency of resistance selection in vitro was low, it resulted in two S. aureus populations of FabI mutants, leading to low and high resistance (MICs of 0.5 to 4 g/ml and Ͼ32 g/ml, respectively) (210). In 2010, results from a phase 1 ascending-dose study in healthy human volunteers indicated an elimination half-life of approximately 1 h (218).…”

“…Like for the PDF inhibitors, no drug targeting fatty acid biosynthesis has been developed into an approved antibacterial drug outside the mycobacterial arena, although several research groups have conducted screening campaigns using this as a target (207)(208)(209)(210)(211). At GSK, lead compounds were identified from HTS assays for two enzymes involved in fatty acid biosynthesis: FabH, the ␤-ketoacyl-acyl carrier protein synthase III, and the enoyl-acyl carrier protein (ACP) reductase FabI (202).…”

Antimicrobial Resistance in Neisseria gonorrhoeae in the 21st Century: Past, Evolution, and Future

“…Notably, several antimicrobials or other compounds, using new targets or mechanisms, were recently developed, and several have shown high in vitro activities against gonococcal isolates. These include novel inhibitors of protein synthesis, e.g., pleuromutilin BC-3781 (318,319) and the boron-containing inhibitor AN3365 (320,321); novel inhibitors of bacterial topoisomerases that target regions different from the fluoroquinolone-binding sites (322,323), such as VT12-008911 (324) and AZD0914 (323,325,326); FabI inhibitors, such as MUT056399 (327,328); noncytotoxic nanomaterials (329); inhibitors of efflux pumps, particularly coadministered with appropriate antimicrobials, that increase the susceptibility to certain antimicrobials, the innate host defense, and toxic metabolites (234,260,330); LpxC inhibitors (331); molecules mimicking host defensins; host defense peptides, such as LL-37 (multifunctional cathelicidin peptide) (332); and IL-12 NanoCap, which is a biodegradable sustained-release formulation of human interleukin 12 that aims to be a therapeutic vaccine against N. gonorrhoeae (TherapyX Inc.). Several of these novel antimicrobials or other types of compounds deserve further attention for their potential use as future treatments for gonorrhea.…”