Infection and Drug Resistance (May 2023)

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

  • Cao B,
  • Mijiti X,
  • Deng LL,
  • Wang Q,
  • Yu JJ,
  • Anwaierjiang A,
  • Qian C,
  • Li M,
  • Fang DA,
  • Jiang Y,
  • Zhao LL,
  • Zhao X,
  • Wan K,
  • Liu H,
  • Li G,
  • Yuan X

Journal volume & issue
Vol. Volume 16
pp. 3117 – 3135

Abstract

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Bin Cao,1,2,* Xiaokaiti Mijiti,3,* Le-Le Deng,2,4 Quan Wang,3 Jin-Jie Yu,1,2 Aiketaguli Anwaierjiang,5 Chengyu Qian,2,6 Machao Li,2 Dan-Ang Fang,2,6 Yi Jiang,2 Li-Li Zhao,2 Xiuqin Zhao,2 Kanglin Wan,2 Haican Liu,2 Guilian Li,2 Xiuqin Yuan1 1School of Public Health, University of South China, Hengyang, 421001, People’s Republic of China; 2State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, People’s Republic of China; 3The Eighth Affiliated Hospital of Xinjiang Medical University, Urumqi, 830000, People’s Republic of China; 4National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People’s Republic of China; 5College of Xinjiang Uyghur Medicine, Hetian, 848000, People’s Republic of China; 6Wenzhou Key Laboratory of Sanitary Microbiology, Key Laboratory of Laboratory Medicine, Ministry of Education, China, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiuqin Yuan; Guilian Li, Email [email protected]; [email protected]: 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 (INHR) 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 (ETHR) 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 (INHRETHR) 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 INHR, ETHR, and INHRETHR 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 INHR and/or ETHR 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

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