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

M M Islam; Y Tan; H M A Hameed; Z Liu; C Chhotaray; Y Liu; Z Lu; X Cai; Y Tang; Y Gao; G Surineni; X Li; S Tan; L Guo; X Cai; W W Yew; J Liu; N Zhong; T Zhang

doi:10.1016/j.cmi.2018.12.008

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

Clin Microbiol Infect. 2019 Aug;25(8):1041.e1-1041.e7. doi: 10.1016/j.cmi.2018.12.008. Epub 2018 Dec 22.

Authors

M M Islam¹, Y Tan², H M A Hameed¹, Z Liu³, C Chhotaray¹, Y Liu⁴, Z Lu³, X Cai², Y Tang⁴, Y Gao¹, G Surineni¹, X Li², S Tan², L Guo¹, X Cai¹, W W Yew⁵, J Liu², N Zhong⁶, T Zhang⁷

Affiliations

¹ State Key Laboratory of Respiratory Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; University of Chinese Academy of Sciences, Beijing, China.
² State Key Laboratory of Respiratory Disease, Department of Clinical Laboratory, Guangzhou Chest Hospital, Guangzhou, China.
³ State Key Laboratory of Respiratory Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
⁴ State Key Laboratory of Respiratory Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; Institute of Physical Science and Information Technology, Anhui University, Hefei, China.
⁵ Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong, China.
⁶ State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
⁷ State Key Laboratory of Respiratory Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; University of Chinese Academy of Sciences, Beijing, China; State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. Electronic address: zhang_tianyu@gibh.ac.cn.

PMID: 30583053
DOI: 10.1016/j.cmi.2018.12.008

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^RM. 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^RM. tuberculosis isolates showed no known mutation related to PTO^R genes, so uncovered resistance mechanism(s) of prothionamide exist.

Keywords: Cross-resistance; Isoniazid; Multidrug-resistance; Mutation; Mycobacterium tuberculosis; Prothionamide.

MeSH terms

Antitubercular Agents / pharmacology*
Bacterial Proteins / genetics
Drug Resistance, Multiple, Bacterial / genetics*
Genotype
Humans
Isoniazid / pharmacology*
Microbial Sensitivity Tests
Mutation
Mycobacterium tuberculosis / drug effects*
Mycobacterium tuberculosis / genetics*
Promoter Regions, Genetic
Prothionamide / pharmacology*
Sequence Analysis, DNA
Tuberculosis, Multidrug-Resistant / microbiology

Substances

Antitubercular Agents
Bacterial Proteins
Prothionamide
Isoniazid