Isoniazid resistance-conferring mutations are associated with highly variable phenotypic resistance.

Area of Science:

• Microbiology
• Genetics
• Pharmacology

Background:

• High-dose isoniazid is recommended for multidrug-resistant tuberculosis (MDR-TB) with *inhA* mutations.
• Evidence for genotypic-phenotypic concordance in isoniazid resistance is limited.
• This study investigates genetic mutations linked to high-level isoniazid resistance.

Purpose of the Study:

• Identify genetic mutations associated with high-level phenotypic isoniazid resistance in MDR-TB.
• Evaluate the genotypic-phenotypic concordance of *inhA* and *katG* mutations.
• Clarify the resistance profiles of *inhA* and *katG* mutations in clinical isolates.

Main Methods:

• Whole-genome sequencing of 52 clinical MDR-TB isolates.
• Minimum inhibitory concentration (MIC) testing using MGIT-based methods.
• Analysis of MIC distributions and overlap indices for mutation profiles.

Main Results:

• *InhA* mutations showed unexpectedly high MICs (mean 33.64 µg/ml) and high overlap with *inhA* + *katG* mutations (eta=0.45).
• *katG* mutations primarily conferred moderate-level resistance (mean 6.79 µg/ml), contrary to expectations.
• 50% of *InhA* mutants and 83.3% of *katG* mutants exhibited high and moderate resistance, respectively.

Conclusions:

• *InhA* mutations are associated with unexpectedly high isoniazid resistance levels.
• *katG* mutations are more commonly linked to moderate-level resistance than high-level resistance.
• Findings challenge existing assumptions about genotypic-phenotypic correlations in MDR-TB treatment.