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.

Public Health Relevance

The prevalence of antibiotic-resistant infections has risen to a level that requires urgent measures. The goal of our research is to develop new approaches to block the indispensable methylerythritol phosphate pathway to isoprenoids in human pathogens. We will pursue studies to understand unique aspects of catalysis and regulatory mechanisms that can be exploited for new antibiotic development.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM084998-09S1
Application #
9993838
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Bond, Michelle Rueffer
Project Start
2010-08-01
Project End
2020-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
9
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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; 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
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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