Activity of AFN-1252, a novel FabI inhibitor, against Staphylococcus aureus in an in vitro pharmacodynamic model simulating human pharmacokinetics

Brian T Tsuji,Yoriko Harigaya,Alan J Lesse,Alan Forrest,Dung Ngo

doi:10.1179/1973947812y.0000000060

Abstract

AFN-1252, a potent enoyl-ACP reductase (FabI) inhibitor, is under development for the treatment of Staphylococcus aureus infections. The activity of AFN-1252 against two isolates of S. aureus, MSSA 26213 and MRSA S186, was studied in an in vitro pharmacodynamic model simulating AFN-1252 pharmacokinetics in man. Reductions in bacterial viable count over the first 6 hours were generally 1–2 logs and maximal reductions in viable count were generally achieved at fAUC/MIC ratios of 100–200. Maximum reductions in viable count against MSSA 29213 and MRSA S186 were approximately 4 logs, achieved by 450 mg q12h (fAUC/MIC = 1875) dosing at 28 hours. Staphylococcal resistance to AFN-1252 did not develop throughout the 48-hour experiments. As multidrug resistance continues to increase, these studies support the continued investigation of AFN-1252 as a targeted therapeutic for staphylococcal infections.

Highlights

The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) to newer antibacterial agents, in both community and healthcare settings, is a serious worldwide concern as therapeutic options are limited
Greater reductions in viable count were observed with q12h regimens than corresponding q24h regimens, against both methicillin-susceptible S. aureus (MSSA) 29213 and MRSA S186 at 24 and 48 hours
AFN-1252 is a highly potent and specific inhibitor of FabI with exquisite activity against staphylococci in extensive MIC studies,[2,3,4] and superior activity to linezolid in the MRSA murine thigh lesion model.[5]

Summary

Introduction

The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) to newer antibacterial agents, in both community and healthcare settings, is a serious worldwide concern as therapeutic options are limited. There is a need for new antimicrobials possessing potent activity against this pathogen. Bacterial fatty acid biosynthesis (FASII) is a relatively new and unexploited target for antimicrobial treatment of S. aureus.[1] AFN-1252, a potent inhibitor of staphylococcal enoyl-acyl carrier protein (enoyl-ACP) reductase (FabI), a critical enzyme required for bacterial FASII, is being developed by Affinium Pharmaceuticals, Inc. AFN-1252 exhibits targeted and highly potent activity against Staphylococcus spp., with typical minimum inhibitory concentration (MIC90) values of 0.008–0.015 mg/l, up to 3 log reductions in. The objective of this study was to utilize an in vitro pharmacodynamic model simulating human pharmacokinetics to evaluate potential therapeutic regimens of AFN-1252 against S. aureus, including both methicillin-susceptible S. aureus (MSSA) and MRSA

Objectives

Methods

Results

Conclusion