InhA gene

The most common mechanism of isoniazid resistance is the mycobacteria s formation of mutations in catalase-peroxidase KatG, the enzyme that is responsible for activation of isoniazid. Another resistance mechanism is through a missense mutation related to the inhA gene involved in mycolic acid biosynthesis. 

Isoniazid (INH) Inhibits mycolic acid synthesis high level resistance—deletions in katG gene (encodes catalase needed for INH bioactivation) low-level resistance—deletions in inhA gene (encodes acyl carrier protein, the target ). Hepatitis (age-dependent), peripheral neuritis (use vitamin B6), hemolysis in G6PD deficiency, SLE in slow acetylators (rare)... 

Other sites of mutation associated with INH resistance include the inhA gene, which codes for the enoyl-ACP reductase, the putative target for activated INH. Since this type of resistance is to the activated drug and the activation of a prodrug, this mechanism of resistance will not be discussed in detail here. The combination of KatG and inhA mutations account for approximately 80% of all INH-resistant clinical isolates. The remaining resistance phenotypes have yet to be identified. 

The final step in each round of fatty acyl elongation in E. coli is the NADH-dependent reduction of the trans double bond, catalyzed by the homotetrameric (subunit mass of 29 kDa) NADH-dependent enoyl-ACP reductase I (encoded by fabl). The Fabl amino acid sequence is similar (34% identical) to the product of a gene (called inhA) from mycobacteria. InhA is involved in mycolic acid biosynthesis (A. Banerjee, 1994). The synthesis of these unusual 70-80 carbon mycobacterial acids requires a pathway composed of enzymes essentially identical to those of fatty acid synthesis. Missense mutations within the inhA gene result in resistance to the anti-tuberculosis drugs, isoniazid and ethionamide. The crystal structures of Fabl and InhA have been solved, and are virtually superimposable for most... 

The mechanism of high-level INH resistance of M tuberculosis is (A) Formation of drug-inactivating A-acetyltransferase Reduced expression of the katG gene Decreased intracellular accumulation of INH Mutation in the inhA gene Change in the pathway of mycolic acid synthesis... 

Mutations in the kcUG gene result in the underproduction of mycobacterial catalase, an enzyme that bioactivates INH. facilitating its interaction with its target, keto-acyl carrier protein synthetase. The result is high-level resistance to isoniazid but without cross-resistance to pyrazinamide. Mutations in the inhA gene result in low-level resistance, with cross-resistance to pyrazinamide. The answer is (B). 

A Banerjee, E Dubnau, A Quemard, V Balasubramanian, KS Um, T Wilson, D Collins, G de Lisle, WR Jacobs Jr. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science 263 227-230, 1994. 

Musser JM, Kapur V, Wilhams DL, Kreiswirth BN, van Soolingen D, van Embden JD. Characterization of the catalase-peroxidase gene (katG) and inhA locus in isoniazid-resistant and -susceptible strains of Mycobacterium tuberculosis by automated DNA sequencing restricted array of mutatins associated with drag re- 45. sistance. J. Infect. Dis. 1996 173 196-202. 

Resistance to INH generally occurs when the dmg is administered alone for 3 months and is caused mainly by the absence of the gene encoding the catalase-peroxidase katC, which prevents activation of the dmg. Mutations in InhA have also been identified and postulated as a reason for resistance to the dmg. 

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