We intend to develop antibacterials that are different from previous chemical classes and that act on entirely new targets. In prior work we identified a series of tetrahydro-?-carbolines that are potent inhibitors of a novel, broad-spectrum antibacterial target from E. coli, phosphopantetheine adenyl transferease (PPAT). PPAT catalyzes a rate-limiting step in the Coenzyme A (CoA) biosynthetic pathway in bacteria. We will develop the tetrahydro-?-carboline series into antibacterial agents with broad-spectrum antibacterial activity and in vivo efficacy. This will be accomplished by using rational and structure-based drug design to increase the antibacterial activity of this series and by applying a battery of biochemical and biological assays to identify compounds that achieve the following specific aims: (1) optimize potency on S. aureus PPAT for broad-spectrum activity; (2) identify compounds with antibacterial activity suitable for in vivo testing; and (3) identify compounds that are effective in an in vivo model of infection. Compounds that exhibit in vivo efficacy, low toxicity, and favorable in vitro ADME properties will progress to lead optimization in Phase II as in vivo-validated leads. Such leads have the potential to become the first antibiotics to target the PPAT enzyme or the CoA biosynthetic pathway and to be effective on antibiotic-resistant strains of a broad spectrum of pathogens. The development of an entirely new chemical class of antibiotics acting on a new target is expected to have an enormous impact on the treatment of resistant infections. ? ?
