4FS3

Crystal structure of Staphylococcus aureus enoyl-ACP reductase in complex with NADP and AFN-1252

Summary for 4FS3

• Entry DOI: 10.2210/pdb4fs3/pdb
• Descriptor: Enoyl-[acyl-carrier-protein] reductase [NADPH] FabI, [[(2R,3S,4R,5R)-5-(3-aminocarbonyl-4H-pyridin-1-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-oxidanyl-3-phosphonooxy-oxolan-2-yl]methyl hydrogen phosphate, N-methyl-N-[(3-methyl-1-benzofuran-2-yl)methyl]-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)propanamide, ... (4 entities in total)
• Functional Keywords: rossmann fold, short chain dehydrogenase, nadph binding, oxidoreductase
• Biological source: Staphylococcus aureus subsp. aureus
• Total number of polymer chains: 1
• Total formula weight: 29147.76

Authors

Kaplan, N.,Yethon, J.,Bardouniotis, E.,Thalakada, R.,Albert, M.,Awrey, D.E.,Romanov, V.,Dorsey, M.,Ramnauth, J.,Clarke, T.E.,Schmid, M.B.,Berman, J.,Pauls, H.W. (deposition date: 2012-06-26, release date: 2012-09-19, Last modification date: 2023-09-13)

Primary citation

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.
Mode of Action, In Vitro Activity, and In Vivo Efficacy of AFN-1252, a Selective Antistaphylococcal FabI Inhibitor.
Antimicrob.Agents Chemother., 56:5865-5874, 2012

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.

PubMed: 22948878
DOI: 10.1128/AAC.01411-12

Experimental method

X-RAY DIFFRACTION (1.8 Å)