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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Jones, Warren
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Johns Hopkins University
Schools of Medicine
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Sanders, Sara; Bartee, David; Harrison, Mackenzie J et al. (2018) Growth medium-dependent antimicrobial activity of early stage MEP pathway inhibitors. PLoS One 13:e0197638
Bartee, David; Freel Meyers, Caren L (2018) Toward Understanding the Chemistry and Biology of 1-Deoxy-d-xylulose 5-Phosphate (DXP) Synthase: A Unique Antimicrobial Target at the Heart of Bacterial Metabolism. Acc Chem Res 51:2546-2555
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Bartee, David; Wheadon, Michael J; Freel Meyers, Caren L (2018) Synthesis and Evaluation of Fluoroalkyl Phosphonyl Analogues of 2- C-Methylerythritol Phosphate as Substrates and Inhibitors of IspD from Human Pathogens. J Org Chem 83:9580-9591
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Nemeria, Natalia S; Shome, Brateen; DeColli, Alicia A et al. (2016) Competence of Thiamin Diphosphate-Dependent Enzymes with 2'-Methoxythiamin Diphosphate Derived from Bacimethrin, a Naturally Occurring Thiamin Anti-vitamin. Biochemistry 55:1135-48
Bartee, David; Morris, Francine; Al-Khouja, Amer et al. (2015) Hydroxybenzaldoximes Are D-GAP-Competitive Inhibitors of E. coli 1-Deoxy-D-Xylulose-5-Phosphate Synthase. Chembiochem 16:1771-81

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