FIG. 9.

Proposed mechanism of action of INH and ETH. INH and ETH are both prodrugs that are activated by the catalase-peroxidase KatG or the monooxygenase EthA, respectively. The activated forms react with NAD⁺ to form an INH-NAD or ETH-NAD adduct. These adducts inhibit the common target InhA, the NADH-dependent enoyl-ACP reductase of the fatty acid synthase type II system, resulting in mycolic acid biosynthesis inhibition and cell lysis. Resistance to INH or ETH is associated with recessive mutations in the genes encoding the activators of the drugs, katG and ethA, respectively, which prevent drug activation. Coresistance to INH and ETH is associated with dominant mutations in the gene encoding the common target of the drugs, inhA, which result in target amplification or target modification. A novel mechanism of coresistance to INH and ETH is by recessive mutations in ndh, which increase the NADH intracellular concentration and cause resistance by competitively inhibiting the binding of the INH-NAD or ETH-NAD adduct to InhA. This working model accounts for all known resistance phenotypes that have been transferred from drug-sensitive to drug-resistant strains to date.