The Methylerythritol Phosphate Pathway: Promising Drug Targets in the Fight against Tuberculosis

Wang, Xu; Dowd, Cynthia S.

doi:10.1021/acsinfecdis.7b00176

Cited by 48 publications

(48 citation statements)

References 169 publications

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“…1-Deoxy-D-xylulose 5-phosphate synthase (DXPS), 3 an essential enzyme in bacterial central metabolism, catalyzes the formation of DXP, which is an intermediate in isoprenoid, pyridoxal phosphate, and thiamine diphosphate (ThDP) biosyntheses (1)(2)(3)(4)(5). DXP is not a biosynthetic intermediate utilized by humans; therefore, DXPS is an attractive anti-infective target.…”

mentioning

confidence: 99%

X-ray crystallography–based structural elucidation of enzyme-bound intermediates along the 1-deoxy-d-xylulose 5-phosphate synthase reaction coordinate

Chen

DeColli

Meyers

et al. 2019

Journal of Biological Chemistry

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Edited by Joseph M. Jez This work was supported by National Institutes of Health Grants R35 GM126982 (to C. L. D.) and R01 GM084998 (C. L. F. M.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This article contains Figs. S1-S13 and Tables S1-S4. The atomic coordinates and structure factors (codes 6OUV and 6OUW) have been deposited in the Protein Data Bank (http://wwpdb.org/).

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confidence: 99%

X-ray crystallography–based structural elucidation of enzyme-bound intermediates along the 1-deoxy-d-xylulose 5-phosphate synthase reaction coordinate

Chen

DeColli

Meyers

et al. 2019

Journal of Biological Chemistry

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“…26 Many secondary metabolites of IPP and DMAPP are involved in the changes in MTB membrane properties, electron transport in the respiratory chain, and synthesis of polyprenyl phosphates that are critical for the MTB cell wall. 27 In this study, MDR-TB showed a significant up-regulation of DX levels compared to DS-TB and HC. We speculated that the MEP pathway of MDR-MTB was more active, thereby enhancing the viability and resistance of the strain.…”

Section: Discussionmentioning

confidence: 50%

The novel potential biomarkers for multidrug-resistance tuberculosis using UPLC-Q-TOF-MS

Huang

Han

Chen

et al. 2020

Exp Biol Med (Maywood)

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The lack of rapid and efficient diagnostics impedes largely the epidemic control of multidrug-resistant tuberculosis, and might misguide the therapeutic strategies as well. This study aimed to identify novel multidrug-resistant tuberculosis biomarkers to improve the early intervention, symptomatic treatment and control of the prevalence of multidrug-resistant tuberculosis. The serum small molecule metabolites in healthy controls, patients with drug-susceptible tuberculosis, and patients with multidrug-resistant tuberculosis were screened using ultra-high-performance liquid chromatography combined with quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS). The differentially abundant metabolites were filtered out through multidimensional statistical analysis and bioinformatics analysis. Compared with drug-susceptible tuberculosis patients and healthy controls, the levels of 13 metabolites in multidrug-resistant tuberculosis patients altered. Among them, the most significant changes were found in N1-Methyl-2-pyridone-5-carboxamide (N1M2P5C), 1-Myristoyl-sn-glycerol-3-phosphocholine (MG3P), Caprylic acid (CA), and D-Xylulose (DX). And a multidrug-resistant tuberculosis/drug-susceptible tuberculosis differential diagnostic model was built based on these four metabolites, achieved the accuracy, sensitivity, and specificity of 0.928, 86.7%, and 86.7%, respectively. The enrichment analysis of metabolic pathways showed that the phospholipid remodeling of cell membranes was active in multidrug-resistant tuberculosis patients. In addition, in patients with tuberculosis, the metabolites of dipalmitoyl phosphatidylcholine (DPPC), a major component of pulmonary surfactant, were down-regulated. N1M2P5C, MG3P, CA, and DX may have the potential to serve as novel multidrug-resistant tuberculosis biomarkers. This research provides a preliminary experimental basis to further investigate potential multidrug-resistant tuberculosis biomarkers. Impact statement The MDR-TB incidence remains high, making the effective control of TB epidemic yet challenging. Rapid and accurate diagnosis is vitally important for improving the therapeutic efficacy and controlling the prevalence of drug resistance TB. Metabolomics has dramatic potential to distinguish MDR-TB and DS-TB. N1M2P5C, MG3P, CA, and DX that we identified in this study might have potential as novel MDR-TB biomarkers. The phospholipid remodeling of cell membranes was highly active in MDR-TB. The DPPC metabolites in TB were significantly down-regulated. This work aimed to investigate potential MDR-TB biomarkers to enhance the clinical diagnostic efficacy. The metabolic pathway distinctly altered in MDR-TB might provide novel targets to develop new anti-TB drugs.

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“…There is renewed interest in PG biosynthesis as a target for anti-TB therapies as multidrug resistance becomes a serious threat (Catalao et al, 2019). In addition, GcpE/IspG (locus II) constitutes part of the methylerythritol phosphate (MEP) pathway which is considered promising targets for the development of antimycobacterial and antiparasitic agents (He et al, 2018;Wang and Dowd, 2018). The findings of these critical genes in this study illustrate the usefulness of our newly constructed transposon in the studies of mycobacteria.…”

Section: Discussionmentioning

confidence: 69%

Construction and Use of Transposon MycoTetOP2 for Isolation of Conditional Mycobacteria Mutants

2020

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Mycobacteria are unique in many aspects of their biology. The development of genetic tools to identify genes critical for their growth by forward genetic analysis holds great promises to advance our understanding of their cellular, physiological and biochemical processes. Here we report the development of a novel transposon, MycoTetOP 2 , to aid the identification of such genes by direct transposon mutagenesis. This mariner-based transposon contains nested anhydrotetracycline (ATc)-inducible promoters to drive transcription outward from both of its ends. In addition, it includes the Escherichia coli R6Kγ origin to facilitate the identification of insertion sites. MycoTetOP 2 was placed in a shuttle plasmid with a temperature-sensitive DNA replication origin in mycobacteria. This allows propagation of mycobacteria harboring the plasmid at a permissive temperature. The resulting population of cells can then be subjected to a temperature shift to select for transposon mutants. This transposon and its delivery system, once constructed, were tested in the fast-growing model Mycobacterium smegmatis and 13 mutants with ATc-dependent growth were isolated. The identification of the insertion sites in these mutants led to nine unique genetic loci with genes critical for essential processes in both M. smegmatis and Mycobacterium tuberculosis. These results demonstrate that MycoTetOP 2 and its delivery vector provide valuable tools for the studies of mycobacteria by forward genetics.

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The Methylerythritol Phosphate Pathway: Promising Drug Targets in the Fight against Tuberculosis

Cited by 48 publications

References 169 publications

X-ray crystallography–based structural elucidation of enzyme-bound intermediates along the 1-deoxy-d-xylulose 5-phosphate synthase reaction coordinate

X-ray crystallography–based structural elucidation of enzyme-bound intermediates along the 1-deoxy-d-xylulose 5-phosphate synthase reaction coordinate

The novel potential biomarkers for multidrug-resistance tuberculosis using UPLC-Q-TOF-MS

Construction and Use of Transposon MycoTetOP2 for Isolation of Conditional Mycobacteria Mutants

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