Contribution of putative efflux pump genes to isoniazid resistance in clinical isolates of Mycobacterium tuberculosis

• Main Authors: Anshika Narang, Astha Giri, Shraddha Gupta, Kushal Garima, Mridula Bose, Mandira Varma-Basil
• Format: Article
• Language: English
• Published: Wolters Kluwer Medknow Publications 2017-01-01
• Series: International Journal of Mycobacteriology
• Subjects: Efflux pumps; isoniazid resistance; Mycobacterium tuberculosis
• Online Access: http://www.ijmyco.org/article.asp?issn=2212-5531;year=2017;volume=6;issue=2;spage=177;epage=183;aulast=Narang

Background: Isoniazid (INH) resistance in Mycobacterium tuberculosis has been mainly attributed to mutations in katG (64%) and inhA (19%). However, 20%–30% resistance to INH cannot be explained by mutations alone. Hence, other mechanisms besides mutations may play a significant role in providing drug resistance. Here, we explored the role of 24 putative efflux pump genes conferring INH-resistance in M. tuberculosis. Materials and Methods: Real-time expression profiling of the efflux pump genes was performed in five INH-susceptible and six high-level INH-resistant clinical isolates of M. tuberculosis exposed to the drug. Isolates were also analyzed for mutations in katG and inhA. Results: Four high-level INH-resistant isolates (minimum inhibitory concentration [MIC] ≥2.5 mg/L) with mutations at codon 315 (AGC-ACC) of katG showed upregulation of one of the efflux genes Rv1634, Rv0849, efpA, or p55. Another high-level INH-resistant isolate (MIC 1.5 mg/L), with no mutations at katG or inhA overexpressed 8/24 efflux genes, namely, Rv1273c, Rv0194, Rv1634, Rv1250, Rv3823c, Rv0507, jefA, and p55. Five of these, namely, Rv0194, Rv1634, Rv1250, Rv0507, and p55 were induced only in resistant isolates. Conclusion: The high number of efflux genes overexpressed in an INH-resistant isolate with no known INH resistance associated mutations, suggests a role for efflux pumps in resistance to this antituberculous agent, with the role of Rv0194 and Rv0507 in INH resistance being reported for the first time.