BACTERIAL DNA POLYMERASES: TARGETS FOR NOVEL ANTIBIOTIC

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DESCRIPTION (Applicant's abstract): The objective of this project is to identify novel drugs to treat antibiotic-resistant Gr+ and Gr- bacterial infections. The work will utilize an unexploited target, the class III bacterial DNA polymerase (pol III). The bacterial pol IIIs are highly conserved enzymes that are required for the synthesis of DNA during chromosomal replication. When an inhibitor of pol III is applied to a growing bacterium, it stops replication, and, thus, like the replication-specific quinolone antibiotics, it is bactericidal. Furthermore, the pol III-selective inhibitors are equally effective against clinically relevant antibiotic-resistant and antibiotic-sensitive pathogens. Therefore, they provide an excellent basis for developing novel agents, which are effective in the treatment of antibiotic-resistant infections. The research plan for the phase I studies proposes to identify novel inhibitors via moderate throughput screening of diverse chemical libraries against three pol IIIs (the Gr- pol III E, and the Gr+ E and C types). The goal of this screening will be to identify one or more novel chemical scaffolds that can be suitably modified for development as new bactericidal drug candidates. Health relatedness: The project exploits a novel target to identify new bactericidal compounds to confront the growing crisis in the therapy of infections caused by antibiotic-resistant bacterial pathogens. PROPOSED COMMERCIAL APPLICATION: Microbiotix will identify bactericidal inhibitors of Gr+ and Gr- pathogens with strong potential for development as broad-spectrum antimicrobials effective in the treatment of problematic antibioticresistant infections. The SBIR phase I study proposes to identify distinct pharmacophores selective for one or more of the three Gr+ and Gr- specific pol Ms. In phase II Microbiotix will chemically modify and further develop these pol III-specific pharmacophores into bona fide drug candidates