Resistance to isoniazid and ethionamide in Mycobacterium tuberculosis: Genes, mutations, and causalities

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Isoniazid (INH) is the cornerstone of tuberculosis (TB) chemotherapy, used for both treatment and prophylaxis of TB. The antimycobacterial activity of INH was discovered in 1952, and almost as soon as its activity was published, the first INH-resistant Mycobacterium tuberculosis strains were reported. INH and its structural analog and second-line anti-TB drug ethionamide (ETH) are pro-drugs. INH is activated by the catalaseperoxidase KatG, while ETH is activated by the monooxygenase EthA. The resulting active species reacts with NAD+ to form an INH-NAD or ETH-NAD adduct, which inhibits the enoyl ACP reductase InhA, leading to mycolic acid biosynthesis inhibition and mycobacterial cell death. The major mechanism of INH resistance is mutation in katG, encoding the activator of INH. One specific KatG variant, S315T, is found in 94% of INH-resistant clinical isolates. The second mechanism of INH resistance is a mutation in the promoter region of inhA (c-15t), which results in inhA overexpression and leads to titration of the drug. Mutations in the inhA open reading frame and promoter region are also the major mechanism of resistance to ETH, found more often in ETH-resistant clinical isolates than mutations in the activator of ETH. Other mechanisms of resistance to INH and ETH include expression changes of the drugs' activators, redox alteration, drug inactivation, and efflux pump activation. In this article, we describe each known mechanism of resistance to INH and ETH and its importance in M. tuberculosis clinical isolates.

Original languageEnglish (US)
Article numberMGM2-0014-2013
JournalMicrobiology Spectrum
Volume2
Issue number4
DOIs
StatePublished - Jan 1 2014

Fingerprint

Ethionamide
tuberculosis
Isoniazid
Mycobacterium tuberculosis
Causality
mutation
drug
Mutation
gene
Genes
Tuberculosis
chemotherapy
Genetic Promoter Regions
Pharmaceutical Preparations
NAD
Mycolic Acids
pump
Prodrugs
Mixed Function Oxygenases
Open Reading Frames

ASJC Scopus subject areas

  • Physiology
  • Ecology
  • Immunology and Microbiology(all)
  • Genetics
  • Microbiology (medical)
  • Cell Biology
  • Infectious Diseases

Cite this

@article{813f8168d99d40268c5692877fde0dbd,
title = "Resistance to isoniazid and ethionamide in Mycobacterium tuberculosis: Genes, mutations, and causalities",
abstract = "Isoniazid (INH) is the cornerstone of tuberculosis (TB) chemotherapy, used for both treatment and prophylaxis of TB. The antimycobacterial activity of INH was discovered in 1952, and almost as soon as its activity was published, the first INH-resistant Mycobacterium tuberculosis strains were reported. INH and its structural analog and second-line anti-TB drug ethionamide (ETH) are pro-drugs. INH is activated by the catalaseperoxidase KatG, while ETH is activated by the monooxygenase EthA. The resulting active species reacts with NAD+ to form an INH-NAD or ETH-NAD adduct, which inhibits the enoyl ACP reductase InhA, leading to mycolic acid biosynthesis inhibition and mycobacterial cell death. The major mechanism of INH resistance is mutation in katG, encoding the activator of INH. One specific KatG variant, S315T, is found in 94{\%} of INH-resistant clinical isolates. The second mechanism of INH resistance is a mutation in the promoter region of inhA (c-15t), which results in inhA overexpression and leads to titration of the drug. Mutations in the inhA open reading frame and promoter region are also the major mechanism of resistance to ETH, found more often in ETH-resistant clinical isolates than mutations in the activator of ETH. Other mechanisms of resistance to INH and ETH include expression changes of the drugs' activators, redox alteration, drug inactivation, and efflux pump activation. In this article, we describe each known mechanism of resistance to INH and ETH and its importance in M. tuberculosis clinical isolates.",
author = "Catherine Vilch{\`e}ze and Jacobs, {William R.}",
year = "2014",
month = "1",
day = "1",
doi = "10.1128/microbiolspec.MGM2-0014-2013",
language = "English (US)",
volume = "2",
journal = "Microbiology spectrum",
issn = "2165-0497",
publisher = "American Society for Microbiology",
number = "4",

}

TY - JOUR

T1 - Resistance to isoniazid and ethionamide in Mycobacterium tuberculosis

T2 - Genes, mutations, and causalities

AU - Vilchèze, Catherine

AU - Jacobs, William R.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Isoniazid (INH) is the cornerstone of tuberculosis (TB) chemotherapy, used for both treatment and prophylaxis of TB. The antimycobacterial activity of INH was discovered in 1952, and almost as soon as its activity was published, the first INH-resistant Mycobacterium tuberculosis strains were reported. INH and its structural analog and second-line anti-TB drug ethionamide (ETH) are pro-drugs. INH is activated by the catalaseperoxidase KatG, while ETH is activated by the monooxygenase EthA. The resulting active species reacts with NAD+ to form an INH-NAD or ETH-NAD adduct, which inhibits the enoyl ACP reductase InhA, leading to mycolic acid biosynthesis inhibition and mycobacterial cell death. The major mechanism of INH resistance is mutation in katG, encoding the activator of INH. One specific KatG variant, S315T, is found in 94% of INH-resistant clinical isolates. The second mechanism of INH resistance is a mutation in the promoter region of inhA (c-15t), which results in inhA overexpression and leads to titration of the drug. Mutations in the inhA open reading frame and promoter region are also the major mechanism of resistance to ETH, found more often in ETH-resistant clinical isolates than mutations in the activator of ETH. Other mechanisms of resistance to INH and ETH include expression changes of the drugs' activators, redox alteration, drug inactivation, and efflux pump activation. In this article, we describe each known mechanism of resistance to INH and ETH and its importance in M. tuberculosis clinical isolates.

AB - Isoniazid (INH) is the cornerstone of tuberculosis (TB) chemotherapy, used for both treatment and prophylaxis of TB. The antimycobacterial activity of INH was discovered in 1952, and almost as soon as its activity was published, the first INH-resistant Mycobacterium tuberculosis strains were reported. INH and its structural analog and second-line anti-TB drug ethionamide (ETH) are pro-drugs. INH is activated by the catalaseperoxidase KatG, while ETH is activated by the monooxygenase EthA. The resulting active species reacts with NAD+ to form an INH-NAD or ETH-NAD adduct, which inhibits the enoyl ACP reductase InhA, leading to mycolic acid biosynthesis inhibition and mycobacterial cell death. The major mechanism of INH resistance is mutation in katG, encoding the activator of INH. One specific KatG variant, S315T, is found in 94% of INH-resistant clinical isolates. The second mechanism of INH resistance is a mutation in the promoter region of inhA (c-15t), which results in inhA overexpression and leads to titration of the drug. Mutations in the inhA open reading frame and promoter region are also the major mechanism of resistance to ETH, found more often in ETH-resistant clinical isolates than mutations in the activator of ETH. Other mechanisms of resistance to INH and ETH include expression changes of the drugs' activators, redox alteration, drug inactivation, and efflux pump activation. In this article, we describe each known mechanism of resistance to INH and ETH and its importance in M. tuberculosis clinical isolates.

UR - http://www.scopus.com/inward/record.url?scp=84954510585&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84954510585&partnerID=8YFLogxK

U2 - 10.1128/microbiolspec.MGM2-0014-2013

DO - 10.1128/microbiolspec.MGM2-0014-2013

M3 - Article

C2 - 26104204

AN - SCOPUS:84954510585

VL - 2

JO - Microbiology spectrum

JF - Microbiology spectrum

SN - 2165-0497

IS - 4

M1 - MGM2-0014-2013

ER -