FabI Inhibitor Program
The Affinium structure-guided drug discovery efforts have produced a library of over 1700 compounds optimized against the S. aureus FabI enzyme. To capitalize on our rich inhibitor library and to develop additional specific-spectrum therapies, 3D FabI protein crystal structures were obtained for additional bacterial species. Our FabI inhibitor library was then screened for inhibition of the FabI enzymes from E. coli, F. tularensis, H. pylori, P. acnes and M. tuberculosis and select compounds were further tested for whole cell inhibition. These inhibition data, together with the FabI 3D structures, were used to generate structure-activity relationships (SAR) for specific inhibition of the tested bacterial species and to formulate plans to optimize the initial leads.
Several preclinical leads specific for F. tularensis were further studied in depth, including tularemia mouse models of infection, preclinical toxicology and human microdosing studies.
These inhibitors, and associated SAR, represent a new class of antibiotics with a unique mechanism of action and are a significant opportunity for multiple products and partnering opportunities. For further details please contact Leisa Dennehy at ldennehy@afnm.com
 [ Click image to enlarge ] FabI-inhibitor co-crystal structures from diverse bacterial species |
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