Detection of novel mutations associated with independent resistance and cross-resistance to isoniazid and prothionamide in Mycobacterium tuberculosis clinical isolates. (August 2019)

• Record Type: Journal Article
• Authors: Islam, M.M.; Tan, Y.; Hameed, H.M.A.; Liu, Z.; Chhotaray, C.; Liu, Y.; Lu, Z.; Cai, X.; Tang, Y.; Gao, Y.; Surineni, G.; Li, X.; Tan, S.; Guo, L.; Cai, X.; Yew, W.W.; Liu, J.; Zhong, N.; Zhang, T.
• Is Part Of: Clinical microbiology and infection. Volume 25:Number 8(2019)
• Page Start: 1041.e1
• Page End: 1041.e7
• Publication Date: 2019-08
• Subjects: Cross-resistance -- Isoniazid -- Multidrug-resistance -- Mutation -- Mycobacterium tuberculosis -- Prothionamide; Medical microbiology -- Periodicals; Diagnostic microbiology -- Periodicals; Communicable diseases -- Periodicals; Infection -- Periodicals; 616.01
• DOI: 10.1016/j.cmi.2018.12.008
• Languages: English
• ISSNs: 1198-743X

Abstract

Abstract: Objectives: Prothionamide, a structural analogue of isoniazid, is used mainly for treating multidrug-resistant tuberculosis (MDR-TB). Both drugs have a common target InhA, so prothionamide can be ineffective against isoniazid-resistant (INH R ) Mycobacterium tuberculosis . We aimed to investigate the prevalence of mutations in katG, ethA, ndh, ethR, mshA, inhA and/or its promoter associated with independent resistance and cross-resistance to INH R and/or prothionamide-resistant (PTO R ) M. tuberculosis isolates. Methods: We sequenced the above genes in 206 M. tuberculosis isolates with susceptibility testing against ten drugs. Results: Of the 173 INH R PTO R isolates, 170 (98.3%) harboured mutations in katG, 111 (64.2%) in ethA, 58 (33.5%) in inhA or its promoter, 5 (2.9%) in ndh, 3 (1.7 %) in ethR and 2 (1.2%) in mshA . Among the 18 INH R PTO S isolates, mutations in katG were found in all of them; one had a mutation in the inhA promoter and another in ndh . Of the five INH S PTO R isolates, four showed mutations in ethA and two in the inhA promoter. Notably, 55 novel non-synonymous mutations were found in them and 20.2% of the PTO R M. tuberculosis isolates harboured no known mutations. Conclusions: This is the first report to investigate cross-resistance between INH R and/or PTO R isolates. Among INH R (94.4% MDR-TB) M. tuberculosis isolates, the high diversity of mutations for independent resistance and cross-resistance with prothionamide highlight the importance of both phenotypic susceptibility and genotypic diagnosis when using it to treat patients with INH R -TB. The high proportion (one-fifth) of PTO R M. tuberculosis isolates showed no known mutation related to PTO R genes, so uncovered resistance mechanism(s) of prothionamide exist. Graphical abstract: Image 1