In vitro activity (MICs and rate of kill) of AFN-1252, a novel FabI inhibitor, in the presence of serum and in combination with other antibiotics

Abstract

AFN-1252 is a novel inhibitor of FabI, an essential enzyme in fatty acid biosynthesis in Staphylococcus spp. AFN-1252 exhibits typical MIC₉₀ values of ⩽0·015 μg/ml against diverse clinical isolates of S. aureus, oral absorption, long elimination half-live and efficacy in animal models. We now report high binding (∼95%) to serum proteins of mouse, rat, dog and humans, associated with an eight-fold increase in minimal inhibitory concentration (MIC) and which may be responsible for the long elimination half-lives on pharmacokinetic studies. Unlike daptomycin, AFN-1252 activity is not reduced in the presence of lung surfactant. AFN-1252 exhibits a short post-antibiotic effect of 1·1 hours against methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) following a 4-hour exposure period. The AFN-1252 unique spectrum of activity is not compromised by interactions with major antibiotic classes, but demonstrates synergy with low concentrations of gentamicin against MSSA and MRSA. These studies support the continued investigation of AFN-1252 as a targeted therapeutic for staphylococcal infections.

Keywords:

• AFN-1252
• Staphylococcus aureus
• FabI inhibitor
• In vitro activities
• Lung surfactant
• Serum binding
• Combinations
• Post-antibiotic effect

We thank Dr George Drusano for assistance in the experimental design and data interpretation of the serum time-kill experiments and Gary E. Zurenko and Roger R. Hinshaw (Micromyx, LLC, Kalamazoo, MI, USA) for their execution. We also thank Dr David Nicolau and Mary Ann Banevicius (Center for Anti-Infective Research & Development Hartford Hospital) for their contributions to the ultrafiltration mouse serum binding assay, and Linh Nguyen, Limei Tao and Alan McIntyre (Charles River Laboratories, Montreal) for the equilibrium dialysis plasma protein binding assays. We finally thank Lauretta Stapert, Dr Chris Pillar and Dr Dean L. Shinabarger (Micromyx, LLC, Kalamazoo, MI, USA) for the lung surfactant MIC assessments. Micron Research Ltd assisted in the preparation of this manuscript.