Isoniazid

Isoniazid itself is not toxic to the bacterial cell, but acts as a prodrug and is activated by the Mycobacterial enzyme KatG, a catalase-peroxidase.  This enzyme prevents the formation of unstable oxygen radicals.  Once activated, isoniazid binds to and inactivates InhA, an enoyl-reductase involved in mycolic acid synthesis.

The inhibition of cell wall lipid synthesis, depletion of nucleic acid pools and metabolic depression contribute to the potency and selectivity.

A missense mutation within the Mycobacterial inhA gene was shown to confer resistance to Isoniazid in M. smegmatis and M. bovis. The wild-type inhA gene also conferred resistance when transferred on a multicopy plasmid vector to M. smegmatis and M. bovis BCG. (Banerjee et al, 1994).

Strategies that exploit the collateral vulnerabilities of drug resistance have the potential to prevent the emergence of drug-resistant pathogens. By applying Whole genome-CRISPRi screens with transcriptional and metabolomic approaches authors generated a genome-wide map of collateral vulnerabilities in an INH^R-katG mutant strain of M. tuberculosis.  Their work shows that changes of physiology of drug-resistant strains generates druggable vulnerabilities that can be exploited (Wang et al, 2024).

Banerjee A et al (1994)  InhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. 263(5144):227-230

Han CD et al (2013)  Isoniazid could be used for antibiotic-loaded bone cement for musculoskeletal tuberculosis: An in vitro study. Clin. Orthop. Relat. Res. 471(7):2400-2406  PMID: 23504536

Johnsson K (1994)  Studies on the mechanism of action of Isoniazid and Ethionamide in the chemotherapy of tuberculosis. Amer. Chem. Soc. Vol 5009-010

Timmins GS and Deretic V (2006)  Mechanisms of action of Isoniazid. Molec. Microbiol. 62(5):1220-1227

Wang X, Jowsey WJ, Cheung CY et al. (2024)  Whole genome CRISPRi screening identifies druggable vulnerabilities in an isoniazid resistant strain of Mycobacterium tuberculosis. Nat.Commun.15:9791