Detection of novel mutations associated with independent resistance and cross-resistance to isoniazid and prothionamide in Mycobacterium tuberculosis clinical isolates

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 (INHR) 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 INHR and/or prothionamide-resistant (PTOR) M. tuberculosis isolates. Methods: We sequenced the above genes in 206 M. tuberculosis isolates with susceptibility testing against ten drugs. Results: Of the 173 INHR PTOR 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 INHR PTOS 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 INHS PTOR 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 PTOR M. tuberculosis isolates harboured no known mutations. Conclusions: This is the first report to investigate cross-resistance between INHR and/or PTOR isolates. Among INHR (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 INHR-TB. The high proportion (one-fifth) of PTOR M. tuberculosis isolates showed no known mutation related to PTOR genes, so uncovered resistance mechanism(s) of prothionamide exist. (C) 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.