The overall objective of this application for an NCDDG grant is to develop new drugs for the treatment of M. avium complex, one of the opportunistic infections that is prevalent in patients with AIDS. The application consists of three projects plus an administrative core. The first project (0001) is a combined synthetic chemistry project that involves the synthesis of a variety of new compounds as inhibitors of key enzymes that are specifically involved in the biosynthesis of the mycobacterial integument. The enzyme targets relate to the arabinogalactan core as well as to the mycolation process. The second project (0002) to be conducted at Colorado State University in the laboratories of Dr. Patrick Brennan and Dr. Michael McNeil, involves the evaluation of new compounds of interest from Project 1 in their M. avium systems. This project will provide critical feedback information for the synthetic program and at the same time also provide mechanism of action information. The complementary interaction with the existing NCDDG under Dr. brennan's direction will also provide timely information on our current enzyme targets as well as indicate potentially worthwhile new targets. Project 0003 will provide the in vitro evaluation of new drug candidates, specifically involving evaluation against a panel of M. avium isolates for bactericidal and bacteriostatic properties. Additional work will involve an examination of the ability of certain new drugs to perturb the bacterial envelope as well as an evaluation of synergy in combination with certain other relevant drugs. The most promising drug candidates will be examined for acute toxicity in mice to establish the highest nontoxic dose prior to their evaluation for efficacy in vivo through an agreement with Dr. Litterst at NIAID. Arrangements have been made for proper interaction and communication between the groups at Southern Research Institute and the group at Colorado State University. A patent rights agreement is attached along with letters from other collaborators.
