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Resistance to Isoniazid and Ethionamide in : Genes, Mutations, and Causalities

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  • Authors: Catherine Vilchèze1, William R. Jacobs JR.2
  • Editors: Graham F. Hatfull3, William R. Jacobs Jr.4
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 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
    • Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0014-2013
  • Received 23 April 2013 Accepted 05 August 2013 Published 04 July 2014
  • 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 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 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 (c-15t), which results in overexpression and leads to titration of the drug. Mutations in the 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 clinical isolates.

  • Citation: Vilchèze C, Jacobs JR. W. 2014. Resistance to Isoniazid and Ethionamide in : Genes, Mutations, and Causalities. Microbiol Spectrum 2(4):MGM2-0014-2013. doi:10.1128/microbiolspec.MGM2-0014-2013.

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/content/journal/microbiolspec/10.1128/microbiolspec.MGM2-0014-2013
2014-07-04
2019-08-18

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 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 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 (c-15t), which results in overexpression and leads to titration of the drug. Mutations in the 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 clinical isolates.

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Resistance to Isoniazid and Ethionamide in : Genes, Mutations, and Causalities
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Citation: Vilchèze C, Jacobs JR. W. 2014. Resistance to isoniazid and ethionamide in : genes, mutations, and causalities. microbiolspec 2(4): doi:10.1128/microbiolspec.MGM2-0014-2013
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FIGURE 1
Early synthetic antituberculosis drugs.
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FIGURE 1

Early synthetic antituberculosis drugs.

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0014-2013
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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 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.

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0014-2013
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FIGURE 3
Relationship among the genes and proteins involved in the resistance to INH and ETH in . 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.
microbiolspec/2/4/MGM2-0014-2013-fig3_thmb.gif
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FIGURE 3

Relationship among the genes and proteins involved in the resistance to INH and ETH in . 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.

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0014-2013
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Resistance to Isoniazid and Ethionamide in : Genes, Mutations, and Causalities
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Citation: Vilchèze C, Jacobs JR. W. 2014. Resistance to isoniazid and ethionamide in : genes, mutations, and causalities. microbiolspec 2(4): doi:10.1128/microbiolspec.MGM2-0014-2013
/content/microbiolspec/10.1128/microbiolspec.MGM2-0014-2013.T1
TABLE 1
Identified mutations in genes other than in INH-resistant strains
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TABLE 1

Identified mutations in genes other than in INH-resistant strains

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0014-2013
/content/microbiolspec/10.1128/microbiolspec.MGM2-0014-2013.T2
TABLE 2
Identified mutations in ETH-resistant strains
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TABLE 2

Identified mutations in ETH-resistant strains

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0014-2013
/content/microbiolspec/10.1128/microbiolspec.MGM2-0014-2013.T3
TABLE 3
Identified mutations in INH-resistant strains
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TABLE 3

Identified mutations in INH-resistant strains

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0014-2013
/content/microbiolspec/10.1128/microbiolspec.MGM2-0014-2013.T4
TABLE 4
Biochemical activity of KatG variants ( 87 , 146 , 167 )
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TABLE 4

Biochemical activity of KatG variants ( 87 , 146 , 167 )

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0014-2013

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