The results of a Phase I SBIR have provided a novel class of inhibitors active against gram-positive (Gr+) bacteria and against DNA polymerase (pol) IIIC and E. This is an ideal scaffold upon which to build a Structure Activity Relationship (SAR) and optimum activity and selectivity. The mechanism of inhibition of this new class of compounds, unlike the anilinouracil (AU) compounds whose mechanism is competitive, and the TIBO reverse transcriptase inhibitors whose mechanism is noncompetitive, appears to be "uncompetitive" inhibition. The data suggest that an entirely new mechanism is involved in inhibition of pol IIIC and E. The new family of compounds displays enough favorable properties (i.e. inhibition of Gr+ DNA polymerases as well as bacteria, low in vitro mammalian toxicity and selectivity for DNA synthesis) to warrant further investigation and chemical modification in order to develop structure activity relationships. Biological assays will guide the SAR development. Designated in vitro lead compounds will proceed to a series of in vivo experiments performed in mice. These will include acute toxicity, pharmacokinetic parameter and antibiotic efficacy studies. In addition, Microbiotix will continue to screen for and develop new scaffolds as DNA replication inhibitors. The SAR development and in vitro and in vivo characterization studies are the subject of this Phase II application.