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

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.