Targeting Non-mammalian Isoprenoid Biosynthesis

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DESCRIPTION (provided by applicant): Resistance of human pathogens to anti-infective agents poses a serious threat to human health and requires sustained efforts to develop new therapies. The essential methylerythritol phosphate (MEP) pathway for isoprenoid biosynthesis is widespread in human pathogens, including some of the most deadly infections caused by M. tuberculosis and P. falciparum. Several of the enzymes in this pathway catalyze unprecedented reactions, making them particularly attractive as targets for the development of selective inhibitors. Our long term goal is to understand catalysis in the MEP pathway toward the development of inhibitors targeting isoprenoid biosynthesis in pathogens. This proposal describes studies to examine three intriguing MEP pathway enzymes, IspG, DXP synthase and IspF. Specific Aims 1 and 3 focus on mechanistic studies and inhibitor development of the enzymes that generate and utilize cyclodiphosphate intermediate, methylerythritol cyclodiphosphate (MEcPP). The goal of Specific Aim 2 is to understand catalysis of DXP synthase in C-N bond formation to generate the medicinally useful hydroxamic acid compound class. Anti-infective agents developed to target these enzymes have the potential to broadly impact the treatment of deadly infectious diseases. PUBLIC HEALTH RELEVANCE: Drug resistance in human pathogens is a global health concern requiring sustained efforts to develop new strategies for treatment of life threatening infections. The proposed studies examine the mechanistically intriguing essential methylerythritol phosphate pathway enzymes which are widespread in human pathogens. Mechanistic studies of these enzymes will lead to the development of new anti-infective agents.