The recent use of Bacillus anthracis as a lethal agent of terrorism in the United States is particularly alarming considering the relatively primitive methods used to distribute the bacterial spores and the fact that ordinary, antibiotic-sensitive strains of the anthrax bacillus were used in the attacks. Although antibiotics such as Ciprofloxacin(r) provided a means for treating the anthrax infections that resulted from these attacks, it is generally appreciated that simple genetic manipulations can render B. anthracis bacteria resistant to any known antibiotic. These recent incidents underscore the urgent need for novel therapeutics that might be used in the event of future terrorist attacks or biological warfare scenarios. The purpose of the work outlined in this Phase I application is to bring to bear on this problem an important new lead-discovery technology, recently developed by Elitra Pharmaceuticals, referred to as the TargetArray. The initial version of the TargetArray, the assembly and validation of which is now nearly complete, consists of an arrayed collection of approximately 400 Staphylococcus aureus strains, each engineered to under-express or over-express individual gene products that are essential for viability or growth of this bacterial organism. Differential expression of essential gene products (potential targets) renders the bacteria selectively more sensitive or resistant to target-specific inhibitors of those gene products. Using proprietary methods developed at Elitra for monitoring depletion or enrichment of individual strains cultured in complex mixtures, the TargetArray will allow us to identify relatively rare compounds that inhibit growth through a target-specific mechanism of action. One Phase I objective is to use this version of the TargetArray immediately to identify novel lead compounds with a spectrum that includes both Bacillus and Staphylococcus. A second objective is to create a Bacillus version of the TargetArray that will facilitate the discovery of narrow-spectrum agents active against B. anthracis.
