Anthrax, according to many military and counterterrorism planners, represents the single greatest biological warfare threat. The long-term goal of this research effort is to develop pharmaceuticals that can be used prophylactically to prevent or to treat infection from Baccilis anthracis. A novel enzyme target, NAD synthetase (NADs), has been identified that is critical to the germination and vegetative life cycle of B. anthracis and thus should be an effective point for inhibiting both the vegetative and spore forms of anthrax. Nicotinamide adenine dinucleotide (NAD+) plays a vital role in many biological processes, including being a cosubstrate for hydride transfer, such as DNA recombination and repair, and for numerous oxidation-reduction reactions. Inhibitors developed against the Bacillis subtilis NADs effectively prevent both the germination and vegetative growth of B. subtilis and B. anthracis. The innovative elements of this research effort are the identification of NADs inhibitors that have the potential attributes to become therapeutic agents. Preliminary results, presented in this application, were obtained by a principle subcontractor (the University of Alabama at Birmingham (UAB) with prior funding from DARPA]. These data suggest a very promising commercial opportunity to develop NADs inhibitors into pharmaceuticals for both military and civilian use. The goals for this Phase I SBIR Grant application, presented below. 1. Use chemistry and rational drug design techniques to synthesize additional model NADs inhibitors. 2. Employ iterative HTS pharmacological screening to determine the biological activity of the synthesized model NADs inhibitors. 3. Apply an in vitro (Caco-2 cells) intestinal absorption model to evaluate the deliverability of the biological active model inhibitors. PROPOSED COMMERCIAL APPLICATIONS: There is significant commercial interest in pharmaceuticals that can be used prophylactically to prevent or to treat infection from Bacillus anthracis for both military and civilian use. A novel enzyme target, NAD synthetase (NADs), has been identified that is critical to the germination and vegetative life cycle of B. anthracis. In addition, other antimicrobial targets of this technology may be of commercial interest including methacillin resistant staphylococcus aureus (MRSA), vancomycin resistant enterococcus (VRE), and virulent strains of yeast.
