Objectives: Prothionamide, a structural analogue of isoniazid, is used mainly for treating multidrugresistant 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.

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