Plasticity of Mycobacterium tuberculosis NADH dehydrogenases and their role in virulence

Catherine Vilchèze, Brian Weinrick, Lawrence W. Leung, William R. Jacobs

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Worldwide control of the tuberculosis (TB) epidemic has not been achieved, and the latest statistics show that the TB problem might be more endemic than previously thought. Although drugs and a TB vaccine are available, TB eradication faces the challenges of increasing occurrences of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis (Mtb) strains. To forestall this trend, the development of drugs targeting novel pathways is actively pursued. Recently, enzymes of the electron transport chain (ETC) have been determined to be the targets of potent antimycobacterial drugs such as bedaquiline. We focused on the three NADH dehydrogenases (Ndh, NdhA, and Nuo) of the Mtb ETC with the purpose of defining their role and essentiality in Mtb. Each NADH dehydrogenase was deleted in both virulent and BSL2-approved Mtb strains, from which the double knockouts ΔndhΔnuoAN and ΔndhAΔnuoAN were constructed. The ΔndhΔndhA double knockout could not be obtained, suggesting that at least one type II NADH dehydrogenase is required for Mtb growth. Δndh and ΔndhΔnuoAN showed growth defects in vitro and in vivo, susceptibility to oxidative stress, and redox alterations, while the phenotypes of ΔndhA, ΔnuoAN, and ΔndhAΔnuoAN were similar to the parental strain. Interestingly, although ΔnuoAN had no phenotype in vivo, ΔndhΔnuoAN was the most severely attenuated strain in mice, suggesting a key role for Nuo in vivo when Ndh is absent. We conclude that Ndh is the main NADH dehydrogenase of Mtb and that compounds that could target both Ndh and Nuo would be good candidates for TB drug development.

Original languageEnglish (US)
Pages (from-to)1599-1604
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number7
DOIs
StatePublished - Feb 13 2018

Fingerprint

NADH Dehydrogenase
Mycobacterium tuberculosis
Virulence
Tuberculosis
Electron Transport
bedaquiline
Extensively Drug-Resistant Tuberculosis
Tuberculosis Vaccines
Pharmaceutical Preparations
Phenotype
Drug Delivery Systems
Growth
Oxidation-Reduction
Oxidative Stress
Enzymes

Keywords

  • Dehydrogenase
  • Essentiality
  • NADH
  • Tuberculosis
  • Virulence

ASJC Scopus subject areas

  • General

Cite this

Plasticity of Mycobacterium tuberculosis NADH dehydrogenases and their role in virulence. / Vilchèze, Catherine; Weinrick, Brian; Leung, Lawrence W.; Jacobs, William R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 7, 13.02.2018, p. 1599-1604.

Research output: Contribution to journalArticle

@article{0b237a7755444c0491daefaf765e09f5,
title = "Plasticity of Mycobacterium tuberculosis NADH dehydrogenases and their role in virulence",
abstract = "Worldwide control of the tuberculosis (TB) epidemic has not been achieved, and the latest statistics show that the TB problem might be more endemic than previously thought. Although drugs and a TB vaccine are available, TB eradication faces the challenges of increasing occurrences of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis (Mtb) strains. To forestall this trend, the development of drugs targeting novel pathways is actively pursued. Recently, enzymes of the electron transport chain (ETC) have been determined to be the targets of potent antimycobacterial drugs such as bedaquiline. We focused on the three NADH dehydrogenases (Ndh, NdhA, and Nuo) of the Mtb ETC with the purpose of defining their role and essentiality in Mtb. Each NADH dehydrogenase was deleted in both virulent and BSL2-approved Mtb strains, from which the double knockouts ΔndhΔnuoAN and ΔndhAΔnuoAN were constructed. The ΔndhΔndhA double knockout could not be obtained, suggesting that at least one type II NADH dehydrogenase is required for Mtb growth. Δndh and ΔndhΔnuoAN showed growth defects in vitro and in vivo, susceptibility to oxidative stress, and redox alterations, while the phenotypes of ΔndhA, ΔnuoAN, and ΔndhAΔnuoAN were similar to the parental strain. Interestingly, although ΔnuoAN had no phenotype in vivo, ΔndhΔnuoAN was the most severely attenuated strain in mice, suggesting a key role for Nuo in vivo when Ndh is absent. We conclude that Ndh is the main NADH dehydrogenase of Mtb and that compounds that could target both Ndh and Nuo would be good candidates for TB drug development.",
keywords = "Dehydrogenase, Essentiality, NADH, Tuberculosis, Virulence",
author = "Catherine Vilch{\`e}ze and Brian Weinrick and Leung, {Lawrence W.} and Jacobs, {William R.}",
year = "2018",
month = "2",
day = "13",
doi = "10.1073/pnas.1721545115",
language = "English (US)",
volume = "115",
pages = "1599--1604",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "7",

}

TY - JOUR

T1 - Plasticity of Mycobacterium tuberculosis NADH dehydrogenases and their role in virulence

AU - Vilchèze, Catherine

AU - Weinrick, Brian

AU - Leung, Lawrence W.

AU - Jacobs, William R.

PY - 2018/2/13

Y1 - 2018/2/13

N2 - Worldwide control of the tuberculosis (TB) epidemic has not been achieved, and the latest statistics show that the TB problem might be more endemic than previously thought. Although drugs and a TB vaccine are available, TB eradication faces the challenges of increasing occurrences of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis (Mtb) strains. To forestall this trend, the development of drugs targeting novel pathways is actively pursued. Recently, enzymes of the electron transport chain (ETC) have been determined to be the targets of potent antimycobacterial drugs such as bedaquiline. We focused on the three NADH dehydrogenases (Ndh, NdhA, and Nuo) of the Mtb ETC with the purpose of defining their role and essentiality in Mtb. Each NADH dehydrogenase was deleted in both virulent and BSL2-approved Mtb strains, from which the double knockouts ΔndhΔnuoAN and ΔndhAΔnuoAN were constructed. The ΔndhΔndhA double knockout could not be obtained, suggesting that at least one type II NADH dehydrogenase is required for Mtb growth. Δndh and ΔndhΔnuoAN showed growth defects in vitro and in vivo, susceptibility to oxidative stress, and redox alterations, while the phenotypes of ΔndhA, ΔnuoAN, and ΔndhAΔnuoAN were similar to the parental strain. Interestingly, although ΔnuoAN had no phenotype in vivo, ΔndhΔnuoAN was the most severely attenuated strain in mice, suggesting a key role for Nuo in vivo when Ndh is absent. We conclude that Ndh is the main NADH dehydrogenase of Mtb and that compounds that could target both Ndh and Nuo would be good candidates for TB drug development.

AB - Worldwide control of the tuberculosis (TB) epidemic has not been achieved, and the latest statistics show that the TB problem might be more endemic than previously thought. Although drugs and a TB vaccine are available, TB eradication faces the challenges of increasing occurrences of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis (Mtb) strains. To forestall this trend, the development of drugs targeting novel pathways is actively pursued. Recently, enzymes of the electron transport chain (ETC) have been determined to be the targets of potent antimycobacterial drugs such as bedaquiline. We focused on the three NADH dehydrogenases (Ndh, NdhA, and Nuo) of the Mtb ETC with the purpose of defining their role and essentiality in Mtb. Each NADH dehydrogenase was deleted in both virulent and BSL2-approved Mtb strains, from which the double knockouts ΔndhΔnuoAN and ΔndhAΔnuoAN were constructed. The ΔndhΔndhA double knockout could not be obtained, suggesting that at least one type II NADH dehydrogenase is required for Mtb growth. Δndh and ΔndhΔnuoAN showed growth defects in vitro and in vivo, susceptibility to oxidative stress, and redox alterations, while the phenotypes of ΔndhA, ΔnuoAN, and ΔndhAΔnuoAN were similar to the parental strain. Interestingly, although ΔnuoAN had no phenotype in vivo, ΔndhΔnuoAN was the most severely attenuated strain in mice, suggesting a key role for Nuo in vivo when Ndh is absent. We conclude that Ndh is the main NADH dehydrogenase of Mtb and that compounds that could target both Ndh and Nuo would be good candidates for TB drug development.

KW - Dehydrogenase

KW - Essentiality

KW - NADH

KW - Tuberculosis

KW - Virulence

UR - http://www.scopus.com/inward/record.url?scp=85042047520&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042047520&partnerID=8YFLogxK

U2 - 10.1073/pnas.1721545115

DO - 10.1073/pnas.1721545115

M3 - Article

C2 - 29382761

AN - SCOPUS:85042047520

VL - 115

SP - 1599

EP - 1604

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 7

ER -