Transition-State Analogue Inhibitors of Dihydrofolate Synthetase for MDR/XDR TB

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DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb) is a notorious pathogen whose increasing resistance to antibiotics and heightened lethality in combination with AIDS makes it a major health concern worldwide. The selection and spread of multiple drug resistant Mtb continued for decades leading to selection and spread of two operationally distinct forms, multiple drug resistant (MDR-TB) and extensively drug resistant (XDR-TB). The estimate for global MDR-TB and XDR-TB cases for 2007 were 500,000 and 40,000 respectively. Given the worldwide epidemic in tuberculosis and emergence of drug resistant strains, eradicating MDR-TB and XDR-TB using the current armamentarium of antimicrobials is untenable. Thus, the discovery of new types of anti-Mtb drugs acting on novel drug targets with no cross-resistance to any existing drugs is urgently needed to combat MDR/XDR-TB. The potential impact of a new antimicrobial to treat MDR/XDR-TB would be expected to be major, potentially affecting hundreds of thousands of patients. Targeting the folate biosynthetic pathway is an established and proven therapeutic strategy in a variety of diseases including cancer, bacterial infections and parasitic infections. In humans, folate requirements must be met entirely from dietary sources. In contrast, Mtb and other bacteria synthesize folates de novo and have enzymes that catalyze the assembly of folate that are absent from humans. One such enzyme in Mtb is dihydrofolate synthetase (Mtb-DHFS) that catalyzes the addition of glutamate to dihydropteroate (DHP) to produce dihydrofolate (DHF). Accordingly, humans completely lack DHFS, but it is essential for the growth of Mtb. Targeting DHFS is therefore a highly attractive strategy for developing therapy for treating MDR/XDR-TB, because (1) DHFS is not involved in cross- resistance to any existing anti-Mtb drugs, and (2) it is predicted that bacterial sanctuary sites could be effectively sterilized using high doses of a DHFS inhibitor to achieve bactericidal concentrations without causing dose-limiting toxicities to the patient. Based on the known catalytic mechanism and structural models of the catalytic and DHP-binding sites in Mtb-DHFS, it is our hypothesis that we will be able to develop potent and selective transition-state analogue inhibitors. Thus, the two-year experimental plan in this SBIR Phase 1 proposal aims to jumpstart the discovery campaign to identify potent and selective inhibitors of Mtb-DHFS. The hypothesis we will test during the 2-year Phase 1 segment is that based on the known catalytic mechanism and structural models of the catalytic and DHP-binding sites, we will be able to develop potent and selective transition-state analogue inhibitors to Mtb-DHFS.