Mode of action, in vitro activity, and in vivo efficacy of AFN-1252, a selective antistaphylococcal FabI inhibitor.

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.

• Authors: Nachum Kaplan, Monique Albert, Donald Awrey, Elias Bardouniotis, Judd Berman, Teresa Clarke, Mandy Dorsey, Barry Hafkin, Jaillal Ramnauth, Vladimir Romanov, Molly B Schmid, Rosanne Thalakada, Jeremy Yethon, Henry W Pauls
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 56 Issue 11 Pg. 5865-74 (Nov 2012) ISSN: 1098-6596 [Electronic] United States
• PMID: 22948878 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• API 1252
• Anti-Bacterial Agents
• Bacterial Proteins
• Benzofurans
• Pyrones
• Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)

Topics

• Administration, Oral
• Animals
• Anti-Bacterial Agents (pharmacology, therapeutic use)
• Bacterial Proteins (antagonists & inhibitors, metabolism)
• Benzofurans (pharmacology, therapeutic use)
• Community-Acquired Infections (drug therapy, microbiology)
• Cross Infection (drug therapy, microbiology)
• Drug Administration Schedule
• Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) (antagonists & inhibitors, metabolism)
• Female
• Humans
• Kinetics
• Mice
• Microbial Sensitivity Tests
• Pyrones (pharmacology, therapeutic use)
• Sepsis (drug therapy, microbiology, mortality)
• Staphylococcal Infections (drug therapy, microbiology)
• Staphylococcus aureus (drug effects, enzymology, growth & development)
• Survival Rate