title: 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.affiliation: Affinium Pharmaceuticals, Inc., Toronto, ON, Canada. nkaplan@afnm.com
authors.forename: Nachum
authors.initials: N
authors.lastname: Kaplan
authors.forename: Monique
authors.initials: M
authors.lastname: Albert
authors.forename: Donald
authors.initials: D
authors.lastname: Awrey
authors.forename: Elias
authors.initials: E
authors.lastname: Bardouniotis
authors.forename: Judd
authors.initials: J
authors.lastname: Berman
authors.forename: Teresa
authors.initials: T
authors.lastname: Clarke
authors.forename: Mandy
authors.initials: M
authors.lastname: Dorsey
authors.forename: Barry
authors.initials: B
authors.lastname: Hafkin
authors.forename: Jaillal
authors.initials: J
authors.lastname: Ramnauth
authors.forename: Vladimir
authors.initials: V
authors.lastname: Romanov
authors.forename: Molly B
authors.initials: MB
authors.lastname: Schmid
authors.forename: Rosanne
authors.initials: R
authors.lastname: Thalakada
authors.forename: Jeremy
authors.initials: J
authors.lastname: Yethon
authors.forename: Henry W
authors.initials: HW
authors.lastname: Pauls
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001572:Benzofurans / Q000494:pharmacology / Q000627:therapeutic use*; D017714:Community-Acquired Infections / Q000188:drug therapy / Q000382:microbiology; D003428:Cross Infection / Q000188:drug therapy / Q000382:microbiology; D004334:Drug Administration Schedule; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D007700:Kinetics; D051379:Mice; D008826:Microbial Sensitivity Tests; D011753:Pyrones / Q000494:pharmacology / Q000627:therapeutic use*; D018805:Sepsis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D015996:Survival Rate
chemical_list: C521531:API 1252; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001572:Benzofurans; D011753:Pyrones; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)