F1-341. Specific Spectrum Activity of AFN-1252 Against Aerobic and Anaerobic Bacterial Pathogens
Session: Poster Session: Fatty Acid Biosynthesis and Protein Biosynthesis Inhibitors
Saturday, October 25, 2008: 12:00 AM
Room: Hall C
Background: AFN-1252 is a potent inhibitor of staphylococcal FabI (enoyl-ACP reductase [ENR]), an essential enzyme in bacterial fatty acid synthesis, and is being developed as an oral and IV agent for staphylococcal infections. Various bacterial species possessing alternate ENR forms may not be susceptible to inhibition by AFN-1252. To further assess the AFN-1252 spectrum, a phylogenetic analysis of bacterial ENR was performed and in vitro activities against staphylococci, anaerobic bacteria, and typical Gram-positive (G+) and Gram-negative (G-) pathogens were determined. Methods: Phylogenetic trees were constructed with PHYLIP 3.52 using protein sequences from the NCBI refseq database. Bacterial strains for AST included ATCC reference strains and clinical isolates from the Affinium and Micromyx collections. MICs were determined using CLSI methods. Results: Four distinct bacterial ENR families (FabI, FabL, FabV, FabK) were delineated by phylogenetic analyses. Of the 42 representative aerobic and anaerobic G+ and G- species analyzed, only 18 species had FabI only. The remainder had alternate or more than one form of ENR. AFN-1252 showed highly potent activity against both susceptible and resistant staphylococcal species but no activity against streptococci, enterococci, common G- pathogens and 25 anaerobic G+ and G- species including typical gut bacteria. Conclusions: The AFN-1252 in vitro spectrum of activity was highly correlated with the presence of an essential, single FabI enzyme in a susceptible species such as Staphylococcus. Species non-susceptible to AFN-1252 had an alternative ENR enzyme or multiple enzyme forms. The lack of activity against common gut and skin flora highlights the potential safety benefits of AFN-1252 and the possibility that adverse effects associated with antimicrobial therapy such as diarrhea, antibiotic induced colitis, C. difficile infections and candidiasis will be much less frequent.
Barry Hafkin, MD1, Dean Shinabarger, PhD2, Debora Sweeney2, Gary Zurenko, MS3, Nachum Kaplan, PhD4, Ronda Schaadt, BS2 and  G. Zurenko,
Affinium Pharmaceuticals Role(s): Research Contractor, Received: Research Grant., (1)Affinium Pharmaceuticals, (2)Micromyx, (3)Micromyx, Kalamazoo, MI, (4)Affinium Pharmaceuticals, Toronto, ON, Canada


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