Analysis of genetic characteristics associated with reduced bedaquiline susceptibility in multidrug-resistant Mycobacterium tuberculosis

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis Pub Date : 2024-10-23 DOI:10.1016/j.tube.2024.102572

Shanshan Wang , Xiao Xiao , Shulan Dong , Jiayi Cao , Sainan Wang , Haiyan Xiong , Xuliang Li , Ge Shao , Yi Hu , Xin Shen

{"title":"Analysis of genetic characteristics associated with reduced bedaquiline susceptibility in multidrug-resistant Mycobacterium tuberculosis","authors":"Shanshan Wang , Xiao Xiao , Shulan Dong , Jiayi Cao , Sainan Wang , Haiyan Xiong , Xuliang Li , Ge Shao , Yi Hu , Xin Shen","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 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.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"149 ","pages":"Article 102572"},"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.

查看原文本刊更多论文

耐多药结核分枝杆菌对贝达喹啉敏感性降低的相关基因特征分析

贝达喹啉（BDQ）在缩短耐多药结核病（MDR-TB）的治疗时间和提高治疗成功率方面显示出疗效，因而得到广泛采用。然而，BDQ 的耐药性已经出现。本研究旨在利用公共数据库来帮助检测耐药菌株，从而确定与 BDQ 易感性下降相关的基因特征。研究人员从开源的 CRyPTIC 数据库中选取了 71 个对 BDQ 产生抗药性的分离株和 929 个对 BDQ 易感的分离株进行分析。变异调用是通过 clockwork 管道进行的。对每个基因突变进行单变量逻辑回归，然后进行 LASSO 回归以进一步选择变异。最终，使用对数2转换的最小抑制浓度值作为因变量，建立了多元线性回归模型，并根据 Akaike 信息标准通过逐步回归对变异选择进行了改进。有 10 个基因突变与 BDQ 易感性降低明显相关，其中包括两个关键基因突变：Rv0678_141_ins_1和Rv1979c_D249E的效应估计值分别为1.76（95 % CI：0.67-2.84）和1.69（95 % CI：0.22-3.17）。其他相关基因包括 Rv2699c_-84_del_1、hsaB_I179T、mmpL9_T241A、pncA_C14R、Rv0373c_G621S、Rv0893c_L27F、Rv1770_A4D 和 Rv3428c_S327C。这项研究发现了十个与对 BDQ 易感性降低有关的基因突变，为制定全面的 BDQ 抗性基因目录提供了参考。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Tuberculosis 医学-呼吸系统

CiteScore

4.60

自引率

3.10%

发文量

审稿时长

49 days

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.