Genetic Characterization Conferred Co-Resistance to Isoniazid and Ethionamide in Mycobacterium tuberculosis Isolates from Southern Xinjiang, China

Background: Ethionamide (ETH), a structural analogue of isoniazid (INH), is used for treating multidrug-resistant tuberculosis (MDR-TB). Due to the common target InhA, INH and ETH showed cross-resistance in M. tuberculosis . This study aimed to explore the INH and ETH resistant profiles and genetic mutations conferring independent INH- or ETH-resistance and INH-ETH cross-resistance in M. tuberculosis circulating in south of Xinjiang, China. Methods: From Sep 2017 to Dec 2018, 312 isolates were included using drug susceptibility testing (DST), spoligotyping, and whole genome sequencing (WGS) to analyze the resistance characteristics for INH and/or ETH. Results: Among the 312 isolates, 185 (58.3%) and 127 (40.7%) belonged to the Beijing family and non-Beijing family, respectively; 90 (28.9%) were INH-resistant (INH R ) with mutation rates of 74.4% in katG , 13.3% in inhA and its promoter, 11.1% in ahpC and its upstream region, 2.2% in ndh , 0.0% in mshA , whilst 34 (10.9%) were ETH-resistant (ETH R ) with mutation rates of 38.2% in ethA , 26.2% in inhA and its promoter, and 5.9% in ndh , 0.0% in ethR or mshA ; and 25 (8.0%) were INH-ETH co-resistant (INH R ETH R ) with mutation rates of 40.0% in inhA and its promoter, and 8% in ndh. katG mutants tended to display high-level resistant to INH; and more inhA and its promoter mutants showed low-level of INH and ETH resistance. The optimal gene combinations by WGS for the prediction of INH R , ETH R , and INH R ETH R were, respectively, katG + inhA and its promoter (sensitivity: 81.11%, specificity: 90.54%), ethA + inhA and its promoter+ ndh (sensitivity: 61.76%, specificity: 76.62%), and inhA and its promoter+ ndh (sensitivity: 48.00%, specificity: 97.65%). Conclusion: This study revealed the high diversity of genetic mutations conferring INH and/or ETH resistance among M. tuberculosis isolates, which would facilitate the study on INH R and/or ETH R mechanisms and provide clues for choosing ETH for MDR treatment and molecular DST methods in south of Xinjiang, China. Keywords: cross-resistance, ethionamide, isoniazid, mutation, Mycobacterium tuberculosis