Targeting Non-mammalian Isoprenoid Biosynthesis

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 DESCRIPTION (provided by applicant): The increasing occurrence of antimicrobial-resistance in infectious diseases poses a serious threat to human health, and demands the development of new antimicrobial therapies. The indispensable methylerythritol phosphate (MEP) pathway to isoprenoids comprises seven enzymatic targets in a wide variety of pathogens, including greater than half of bacterial pathogens prioritized by the CDC as serious or urgent threats to public health. Despite this, only the IspC inhibitor fosmidomycin has advanced through clinical evaluation, highlighting the lack of clinically useful agents targeting this pathway. Our research seeks new approaches to block essential isoprenoid production in human pathogens. The proposed studies will focus on under-developed targets in the MEP pathway, including the first step catalyzed by thiamin diphosphate-dependent 1-deoxy-D-xylulose 5-phosphate (DXP) synthase, and the fifth step catalyzed by cyclodiphosphate synthase IspF. A third area of research will focus on targeting flux through early stage isoprenoid biosynthesis. We will take multidisciplinary approaches to: 1) delineate the unique aspects of DXP synthase catalysis and conformational dynamics that can be exploited for selective inhibitor design, 2) examine a putative feed-forward regulatory mechanism for MEcDP production by IspF as a potential new antimicrobial target, and 3) develop strategies to inhibit flux through the early steps of the MEP pathway using simple substrate analogs. Our research is expected to build our knowledge of the unique enzyme behaviors that represent potential points for pharmacologic intervention, which could lead to the development of new antimicrobial therapies.