{"title":"Analysis of genetic characteristics associated with reduced bedaquiline susceptibility in multidrug-resistant Mycobacterium tuberculosis","authors":"","doi":"10.1016/j.tube.2024.102572","DOIUrl":null,"url":null,"abstract":"<div><div>Bedaquiline (BDQ) has shown efficacy in shortening treatment duration and enhancing treatment success rates for multidrug-resistant tuberculosis (MDR-TB), thereby prompting widespread adoption. However, resistance to BDQ has emerged. This study aimed to identify genetic characteristics associated with decreased susceptibility to BDQ, using a public database to aid in the detection of resistant strains. Seventy-one BDQ-resistant and 929 BDQ-susceptible isolates from the open-source CRyPTIC database were selected for analysis. Variant calling was conducted via the clockwork pipeline. Univariate logistic regression was performed for each gene mutation, followed by LASSO regression for further variant selection. Ultimately, a multiple linear regression model was developed using log<sub>2</sub>-transformed Minimum Inhibitory Concentration values as the dependent variable, with variant selection refined through stepwise regression based on the Akaike Information Criterion. Ten gene mutations were significantly associated with reduced BDQ susceptibility, including two key gene mutations: <em>Rv0678</em>_141_ins_1 and <em>Rv1979c</em>_D249E, with effect estimates of 1.76 (95 % CI: 0.67–2.84) and 1.69 (95 % CI: 0.22–3.17), respectively. Other implicated genes included <em>Rv2699c</em>_-84_del_1, <em>hsaB</em>_I179T, <em>mmpL9</em>_T241A, <em>pncA</em>_C14R, <em>Rv0373c</em>_G621S, <em>Rv0893c</em>_L27F, <em>Rv1770</em>_A4D, and <em>Rv3428c</em>_S327C. This study identified ten gene mutations linked to decreased susceptibility to BDQ, providing a reference for developing a comprehensive catalog of BDQ-resistant genes.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":null,"pages":null},"PeriodicalIF":2.8000,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Tuberculosis","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1472979224000982","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Bedaquiline (BDQ) has shown efficacy in shortening treatment duration and enhancing treatment success rates for multidrug-resistant tuberculosis (MDR-TB), thereby prompting widespread adoption. However, resistance to BDQ has emerged. This study aimed to identify genetic characteristics associated with decreased susceptibility to BDQ, using a public database to aid in the detection of resistant strains. Seventy-one BDQ-resistant and 929 BDQ-susceptible isolates from the open-source CRyPTIC database were selected for analysis. Variant calling was conducted via the clockwork pipeline. Univariate logistic regression was performed for each gene mutation, followed by LASSO regression for further variant selection. Ultimately, a multiple linear regression model was developed using log2-transformed Minimum Inhibitory Concentration values as the dependent variable, with variant selection refined through stepwise regression based on the Akaike Information Criterion. Ten gene mutations were significantly associated with reduced BDQ susceptibility, including two key gene mutations: Rv0678_141_ins_1 and Rv1979c_D249E, with effect estimates of 1.76 (95 % CI: 0.67–2.84) and 1.69 (95 % CI: 0.22–3.17), respectively. Other implicated genes included Rv2699c_-84_del_1, hsaB_I179T, mmpL9_T241A, pncA_C14R, Rv0373c_G621S, Rv0893c_L27F, Rv1770_A4D, and Rv3428c_S327C. This study identified ten gene mutations linked to decreased susceptibility to BDQ, providing a reference for developing a comprehensive catalog of BDQ-resistant genes.
期刊介绍:
Tuberculosis is a speciality journal focusing on basic experimental research on tuberculosis, notably on bacteriological, immunological and pathogenesis aspects of the disease. The journal publishes original research and reviews on the host response and immunology of tuberculosis and the molecular biology, genetics and physiology of the organism, however discourages submissions with a meta-analytical focus (for example, articles based on searches of published articles in public electronic databases, especially where there is lack of evidence of the personal involvement of authors in the generation of such material). We do not publish Clinical Case-Studies.
Areas on which submissions are welcomed include:
-Clinical TrialsDiagnostics-
Antimicrobial resistance-
Immunology-
Leprosy-
Microbiology, including microbial physiology-
Molecular epidemiology-
Non-tuberculous Mycobacteria-
Pathogenesis-
Pathology-
Vaccine development.
This Journal does not accept case-reports.
The resurgence of interest in tuberculosis has accelerated the pace of relevant research and Tuberculosis has grown with it, as the only journal dedicated to experimental biomedical research in tuberculosis.