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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.

Triclosan MIC determination showed that recent Staphylococcus aureus clinical isolates ( n = 100) were highly susceptible to triclosan, with a 50% minimal inhibitory concentration (MIC 50 ) of 0.12 μg/ml and a MIC 90 of 0.25 μg/ml. Staphylococcus epidermidis isolates ( n = 96) were less susceptible, with a MIC 50 of 0.12 μg/ml and a MIC 90 of 8 μg/ml. Decreased susceptibility to triclosan was more prevalent among methicillin-resistant S. epidermidis than among methicillin-sensitive S. epidermidis isolates.