Isoniazid Resistance Mechanisms in Mycobacterium tuberculosis

Isoniazid (INH) remains a cornerstone of first-line therapy for tuberculosis, yet resistance to this drug poses a major obstacle to global control efforts. Isoniazid is a prodrug that requires activation by the catalase-peroxidase enzyme KatG. Once activated, it inhibits the enoyl-acyl carrier protein reductase InhA and disrupts mycolic acid synthesis, compromising the mycobacterial cell wall. Resistance most commonly arises through mutations in katG—particularly the Ser315Thr substitution—which reduce activation of isoniazid and confer high-level resistance. Mutations in the inhA promoter region can elevate InhA expression, leading to low- to moderate-level resistance and cross-resistance with ethionamide. Less frequent mechanisms include alterations in ahpC and ndh that compensate for loss of KatG activity or affect intracellular redox balance, and mutations in genes involved in drug efflux and cell-envelope permeability. The clinical spectrum of resistance spans low- to high-level minimum inhibitory concentrations (MICs), influencing choices for high-dose isoniazid regimens. Genomic studies reveal that combinations of mutations can modulate resistance level and fitness costs, shaping transmission dynamics of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. A comprehensive understanding of these pathways is vital for refinement of molecular diagnostics, optimisation of dosing strategies and development of novel inhibitors to restore isoniazid efficacy.

Research from Nature Portfolio

Recent work has demonstrated that a limited set of high-confidence mutations in katG and the inhA promoter can predict the level of phenotypic isoniazid resistance across diverse clinical isolates. Analysis of whole-genome sequences alongside MIC data showed that the katG Ser315Thr mutation typically yields moderate-level resistance, while the co-occurrence with an inhA promoter mutation drives very high MICs. Isolates harbouring inhA promoter changes alone exhibit a spectrum of low-level resistance, underscoring the need to adjust critical concentrations in diagnostic assays. These findings affirm that targeted mutation panels can stratify resistance levels and guide tailored dosing of isoniazid in MDR-TB management.

Isoniazid Resistance Mechanisms in Mycobacterium tuberculosis publication trend

The graph below shows the total number of articles in isoniazid resistance mechanisms in mycobacterium tuberculosis across all publications each year (not limited to Nature Index journals).

Technical terms

KatG: Mycobacterium tuberculosis catalase-peroxidase enzyme that activates isoniazid.

InhA: Enoyl-acyl carrier protein reductase targeted by activated isoniazid to inhibit mycolic acid synthesis.

Promoter mutation: A DNA change in a gene’s regulatory region that alters the amount of enzyme produced.

Minimum inhibitory concentration (MIC): The lowest drug concentration that prevents visible bacterial growth in vitro.

Resistance-associated variant (RAV): A genetic alteration linked to reduced drug susceptibility.

References

1. In vitro modeling of isoniazid resistance mechanisms in Mycobacterium tuberculosis H37Rv. Frontiers in Microbiology (2023).
2. Isoniazid resistance levels of Mycobacterium tuberculosis can largely be predicted by high-confidence resistance-conferring mutations. Scientific Reports (2018).
3. Isoniazid Resistance in Mycobacterium tuberculosis Is a Heterogeneous Phenotype Composed of Overlapping MIC Distributions with Different Underlying Resistance Mechanisms. Antimicrobial Agents and Chemotherapy (2019).