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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084998-05
Application #
8658103
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Gerratana, Barbara
Project Start
2010-08-01
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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
Bartee, David; Freel Meyers, Caren L (2018) Targeting the Unique Mechanism of Bacterial 1-Deoxy-d-xylulose-5-phosphate Synthase. Biochemistry 57:4349-4356
DeColli, Alicia A; Nemeria, Natalia S; Majumdar, Ananya et al. (2018) Oxidative decarboxylation of pyruvate by 1-deoxy-d-xyulose 5-phosphate synthase, a central metabolic enzyme in bacteria. J Biol Chem 293:10857-10869
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
Sanders, Sara; Vierling, Ryan J; Bartee, David et al. (2017) Challenges and Hallmarks of Establishing Alkylacetylphosphonates as Probes of Bacterial 1-Deoxy-d-xylulose 5-Phosphate Synthase. ACS Infect Dis 3:467-478
Afanador, Gustavo A; Guerra, Alfredo J; Swift, Russell P et al. (2017) A novel lipoate attachment enzyme is shared by Plasmodium and Chlamydia species. Mol Microbiol 106:439-451
Zhou, Jieyu; Yang, Luying; DeColli, Alicia et al. (2017) Conformational dynamics of 1-deoxy-d-xylulose 5-phosphate synthase on ligand binding revealed by H/D exchange MS. Proc Natl Acad Sci U S A 114:9355-9360
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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