Resistance to Isoniazid and Ethionamide in Mycobacterium tuberculosis: Genes, Mutations, and Causalities
- Authors: Catherine Vilchèze1, William R. Jacobs JR.2
- Editors: Graham F. Hatfull3, William R. Jacobs Jr.4
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VIEW AFFILIATIONS HIDE AFFILIATIONSAffiliations: 1: Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; 2: Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; 3: University of Pittsburgh, Pittsburgh, PA; 4: Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY
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Received 23 April 2013 Accepted 05 August 2013 Published 04 July 2014
- Correspondence: W. R. Jacobs, Jr., [email protected]
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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 catalase-peroxidase 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.
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Citation: Vilchèze C, Jacobs JR. W. 2014. Resistance to Isoniazid and Ethionamide in Mycobacterium tuberculosis: Genes, Mutations, and Causalities. Microbiol Spectrum 2(4):MGM2-0014-2013. doi:10.1128/microbiolspec.MGM2-0014-2013.




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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 catalase-peroxidase 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.

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Figures

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FIGURE 1
Early synthetic antituberculosis drugs.

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FIGURE 2
Mechanism of action of INH and ETH. INH and ETH are activated by the catalase peroxidase KatG and monooxygenase EthA, respectively, to form a reactive species that binds to NAD+. The resulting adducts, INH-NAD or ETH-NAD, inhibit the enoyl-ACP reductase InhA of the FASII system, resulting in mycolic acid biosynthesis inhibition.

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FIGURE 3
Relationship among the genes and proteins involved in the resistance to INH and ETH in M. tuberculosis. Connections in red indicate a negative relationship (degradation of an active molecule, negative regulator of an enzyme) that would lead to resistance to INH and/or ETH; in green are positive actions that would increase a strain fitness or susceptibility to the drugs. The dashed line points to an interaction that does not result directly in INH resistance or susceptibility.
Tables

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TABLE 1
Identified mutations in genes other than katG in INH-resistant M. tuberculosis strains a

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TABLE 2
Identified mutations in ETH-resistant M. tuberculosis strains a

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TABLE 3
Identified katG mutations in INH-resistant M. tuberculosis strains a
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