title: In vitro activity (MICs and rate of kill) of AFN-1252, a novel FabI inhibitor, in the presence of serum and in combination with other antibiotics.
abstract: AFN-1252 is a novel inhibitor of FabI, an essential enzyme in fatty acid biosynthesis in Staphylococcus spp. AFN-1252 exhibits typical MIC(90) values of ≤0·015 μg/ml against diverse clinical isolates of S. aureus, oral absorption, long elimination  half-live and efficacy in animal models. We now report high binding (∼95%) to serum proteins of mouse, rat, dog and humans, associated with an eight-fold increase in minimal inhibitory concentration (MIC) and which may be responsible for the long elimination half-lives on pharmacokinetic  studies. Unlike daptomycin, AFN-1252 activity is not reduced in the presence of lung surfactant. AFN-1252 exhibits a short post-antibiotic effect of 1·1 hours against methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) following a 4-hour  exposure period. The AFN-1252 unique spectrum of activity is not compromised by interactions with major antibiotic classes, but demonstrates synergy with low concentrations of gentamicin against MSSA and MRSA. These studies support the continued investigation of AFN-1252 as a targeted therapeutic  for staphylococcal infections.
authors: Affinium Pharmaceuticals, Inc., Toronto, ON M5V 3K2, Canada. nkaplan@afnm.com
authors: Nachum
authors: N
authors: Kaplan
authors: Donald
authors: D
authors: Awrey
authors: Elias
authors: E
authors: Bardouniotis
authors: Judd
authors: J
authors: Berman
authors: Jeremy
authors: J
authors: Yethon
authors: Henry W
authors: HW
authors: Pauls
authors: Barry
authors: B
authors: Hafkin
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood* / Q000494:pharmacology*; D001572:Benzofurans / Q000097:blood* / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism*; D017576:Daptomycin / Q000097:blood / Q000494:pharmacology; D004285:Dogs; D005839:Gentamicins / Q000097:blood / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D008297:Male; D008712:Methicillin / Q000097:blood / Q000494:pharmacology; D016106:Methicillin Resistance / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D011663:Pulmonary Surfactants / Q000378:metabolism; D011753:Pyrones / Q000097:blood* / Q000494:pharmacology*; D051381:Rats; D013203:Staphylococcal Infections / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: C521531:API 1252; D000900:Anti-Bacterial Agents; D001572:Benzofurans; D001798:Blood Proteins; D005839:Gentamicins; D011663:Pulmonary Surfactants; D011753:Pyrones; D017576:Daptomycin; D008712:Methicillin