Identifying isoniazid resistance markers to guide inclusion of high-dose isoniazid in tuberculosis treatment regimens

Abstract

Objectives: Effective use of antibiotics is critical to control the global tuberculosis pandemic. High-dose isoniazid (INH) can be effective in the presence of low-level resistance. We performed a systematic literature review to improve our understanding of the differential impact of genomic Mycobacterium tuberculosis (Mtb) variants on the level of INH resistance. The following online databases were searched: PubMed, Web of Science and Embase. Articles reporting on clinical Mtb isolates with linked genotypic and phenotypic data and reporting INH resistance levels were eligible for inclusion. Methods: All genomic regions reported in the eligible studies were included in the analysis, including: katG, inhA, ahpC, oxyR-ahpC, furA, fabG1, kasA, rv1592c, iniA, iniB, iniC, rv0340, rv2242 and nat. The level of INH resistance was determined by MIC: low-level resistance was defined as 0.1e0.4 mg/mL on liquid and 0.2e1.0 mg/mL on solid media, high-level resistance as >0.4mg/mL on liquid and >1.0 mg/mL on solid media. Results: A total of 1212 records were retrieved of which 46 were included. These 46 studies reported 1697 isolates of which 21% (n ¼ 362) were INH susceptible, 17% (n ¼ 287) had low-level, and 62% (n ¼ 1048) high-level INH resistance. Overall, 24% (n ¼ 402) of isolates were reported as wild type and 76% (n ¼ 1295) had 1 relevant genetic variant. Among 1295 isolates with 1 variant, 78% (n ¼ 1011) had a mutation in the katG gene. Of the 867 isolates with a katG mutation in codon 315, 93% (n ¼ 810) had high-level INH resistance. In contrast, only 50% (n ¼ 72) of the 144 isolates with a katG variant not in the 315-position had high-level resistance. Of the 284 isolates with 1 relevant genetic variant and wild type katG gene, 40% (n ¼ 114) had high-level INH resistance. Conclusions: Presence of a variant in the katG gene is a good marker of high-level INH resistance only if located in codon 315.

Whole-genome sequencing for surveillance of tuberculosis drug resistance and determination of resistance level in China

“…In addition to highlighting variants associated with sub-ECOFF elevations in MICs that may be missed using traditional binary methods, this work also highlighted variants that result in different resistance levels. Whilst high-dose isoniazid and rifampin have been proven effective in treating certain resistant strains [24,25]. This will be meaningful for choosing therapeutic schedules in settings lacking new anti-TB drugs or second-line drugs.…”

Isoniazid Linked to Sulfonate Esters via Hydrazone Functionality: Design, Synthesis, and Evaluation of Antitubercular Activity

“…Following the activation by KatG, INH produces a reactive isonicotinoyl-radical intermediate that quickly forms a covalent adduct with the InhA cofactor NADH [ 6 ]. As mutations in katG reduce the activation of INH and thus yield the most prevalent type of INH resistance, developing direct InhA inhibitors that do not require KatG activation appears as an effective and rational strategy to overcome this resistance problem [ 26 ]. Therefore, we screened our INH-based compounds against InhA to determine if they show their antimycobacterial activity via direct inhibition of this enzyme ( Table 2 ).…”

Addressing Latent Tuberculosis: New Advances in Mimicking the Disease, Discovering Key Targets, and Designing Hit Compounds

“…InhA is part of the fatty acid synthase (FAS)-II system, responsible for the catalysis of the synthesis of fatty acids using Acetyl-CoA [172]. InhA is the target of the first-line drug isoniazid that requires activation from a catalase-peroxidase enzyme, KatG, to act on its target [173,174]. Even though isoniazid is reported as inactive against dormant tuberculosis, [26] Doğan et al screened their new family of thiourea-based derivatives against nutrient starved mycobacteria.…”