Mycobacterium-avium intracellulare is a major opportunistic pathogen of immunosuppressed patients, especially AIDS patients. Until recently, very few effective therapeutic agents active in patients with MAI infection have been identified. Folate metabolism is well-characterized in a number of other organisms and provides a suitable target for therapeutic intervention. Folate metabolism in MAI, however, has not been characterized. To see if antifols would be potentially active as therapeutic agents for the treatment of MAI infection, we are undertaking studies to characterized folate metabolism in this organism. Studies have begun by pulsing MAI cultures with both para-aminobenzoic acid and folic acid as well as other reduced folates. In these studies we have been able to show that MAI can synthesis folates de novo. We are currently evaluating the ability of inhibitors of dihydroptroate synthase, an important enzyme in de novo folate synthesis, to inhibit replication of MAI. Such inhibitors include sulfonamides and dapsone. We are also in the process of having an MAI library made so that the DHPS of the organism can be identified. We would then use this recombinant enzyme to screen for inhibitors of DHPS that would be active against MAI. The goal of these studies is to identify and improve therapeutic agents for the treatment and prevention of mycobacterium- avium intracellular infection.
