Different Contributions of embB and ubiA Mutations to Variable Level of Ethambutol Resistance in Mycobacterium tuberculosis Isolates

IF 2.9 3区医学 Q2 INFECTIOUS DISEASES Infection and Drug Resistance Pub Date : 2024-07-18 DOI:10.2147/idr.s466371

Xiao-tian Nan, Ma-chao Li, Tong-yang Xiao, Hai-can Liu, Shi-qiang Lin, Wei Wang, Cheng Qian, Hao Hang, Gui-lian Li, Xiu-qin Zhao, Kang-Lin Wan, Li-li Zhao

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Abstract

Objective: To explore the association between the variant mutations within embB and ubiA, and the degree of ethambutol (EMB) resistance of Mycobacterium tuberculosis (M. tuberculosis) isolates.
Methods: A total of 146 M. tuberculosis isolates were used to determine the minimum inhibitory concentrations (MICs) of EMB with a 96-well microplate-based assay. The mutations within embB and ubiA among these isolates were identified with DNA sequencing. Moreover, a multivariate regression model and a computer model were established to assess the effects of mutations on EMB resistance.
Results: Our data showed that overall 100 isolates exhibited 28 mutated patterns within the sequenced embB and ubiA. Statistical analysis indicated that embB mutations Met306Val, Met306Ile, Gly406Ala, and Gln497Arg, were strongly associated with EMB resistance. Of these mutations, Met306Val and Gln497Arg were significantly associated with high-level EMB resistance. Almost all multiple mutations occurred in high-level EMB-resistant isolates. Although the mutation within ubiA accompanied with embB mutation presented exclusively in EMB-resistant isolates, four single ubiA mutations (Ala39Glu, Ser173Ala, Trp175Cys, and Val283Leu) leading to protein instability were observed in EMB-susceptible isolates.
Conclusion: This study highlighted the complexity of EMB resistance. Some individual mutations and multiple mutations within embB and ubiA contributed to the different levels of EMB resistance.

Keywords: ethambutol, multidrug-resistant tuberculosis, embB, ubiA, mutations, minimum inhibitory concentration

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embB 和 ubiA 基因突变对结核分枝杆菌乙胺丁醇耐药性不同程度的影响

目的探讨embB和ubiA的变异突变与结核分枝杆菌（M. tuberculosis）分离株对乙胺丁醇（EMB）耐药程度之间的关联：方法：采用 96 孔微孔板检测法测定了 146 株结核分枝杆菌对乙胺丁醇（EMB）的最低抑菌浓度（MIC）。通过 DNA 测序确定了这些分离株中 embB 和 ubiA 的突变情况。此外，还建立了一个多变量回归模型和一个计算机模型，以评估突变对 EMB 耐药性的影响：结果：我们的数据显示，100 个分离株的 embB 和 ubiA 序列共有 28 种突变模式。统计分析表明，embB突变Met306Val、Met306Ile、Gly406Ala和Gln497Arg与EMB抗性密切相关。在这些突变中，Met306Val 和 Gln497Arg 与高水平的 EMB 耐药性显著相关。几乎所有的多重突变都发生在对 EMB 高水平耐药的分离株中。尽管伴随embB突变的ubiA突变仅出现在耐EMB的分离株中，但在易感EMB的分离株中观察到了导致蛋白质不稳定的4个单一ubiA突变（Ala39Glu、Ser173Ala、Trp175Cys和Val283Leu）：本研究强调了 EMB 耐药性的复杂性。关键词：乙胺丁醇；耐多药结核病；embB；ubiA；突变；最低抑制浓度

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Infection and Drug Resistance Medicine-Pharmacology (medical)

CiteScore

5.60

自引率

7.70%

发文量

826

审稿时长

16 weeks

期刊介绍： About Journal Editors Peer Reviewers Articles Article Publishing Charges Aims and Scope Call For Papers ISSN: 1178-6973 Editor-in-Chief: Professor Suresh Antony An international, peer-reviewed, open access journal that focuses on the optimal treatment of infection (bacterial, fungal and viral) and the development and institution of preventative strategies to minimize the development and spread of resistance.