Download MendeleyMode of Action, In Vitro Activity, and In Vivo Efficacy of AFN-1252, a Selective Antistaphylococcal FabI Inhibitor.
Kaplan, N., Albert, M., Awrey, D., Bardouniotis, E., Berman, J., Clarke, T., Dorsey, M., Hafkin, B., Ramnauth, J., Romanov, V., Schmid, M.B., Thalakada, R., Yethon, J., Pauls, H.W.(2012) Antimicrob Agents Chemother 56: 5865-5874
- PubMed: 22948878
- DOI: https://doi.org/10.1128/AAC.01411-12
- Primary Citation of Related Structures:
4FS3 - PubMed Abstract:
The mechanism of action of AFN-1252, a selective inhibitor of Staphylococcus aureus enoyl-acyl carrier protein reductase (FabI), which is involved in fatty acid biosynthesis, was confirmed by using biochemistry, macromolecular synthesis, genetics, and cocrystallization of an AFN-1252-FabI complex. AFN-1252 demonstrated a low propensity for spontaneous resistance development and a time-dependent reduction of the viability of both methicillin-susceptible and methicillin-resistant S. aureus, achieving a ≥2-log(10) reduction in S. aureus counts over 24 h, and was extremely potent against clinical isolates of S. aureus (MIC(90), 0.015 μg/ml) and coagulase-negative staphylococci (MIC(90), 0.12 μg/ml), regardless of their drug resistance, hospital- or community-associated origin, or other clinical subgroup. AFN-1252 was orally available in mouse pharmacokinetic studies, and a single oral dose of 1 mg/kg AFN-1252 was efficacious in a mouse model of septicemia, providing 100% protection from an otherwise lethal peritoneal infection of S. aureus Smith. A median effective dose of 0.15 mg/kg indicated that AFN-1252 was 12 to 24 times more potent than linezolid in the model. These studies, demonstrating a selective mode of action, potent in vitro activity, and in vivo efficacy, support the continued investigation of AFN-1252 as a targeted therapeutic for staphylococcal infections.
Organizational Affiliation:
Affinium Pharmaceuticals, Inc., Toronto, ON, Canada. [email protected]
