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

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

doi:10.2147/IDR.S466371

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

Infect Drug Resist. 2024 Jul 18:17:3125-3132. doi: 10.2147/IDR.S466371. eCollection 2024.

Authors

Xiao-Tian Nan^#¹, Ma-Chao Li^#¹, Tong-Yang Xiao^#², Hai-Can Liu^#¹, Shi-Qiang Lin³, Wei Wang¹, Cheng Qian⁴, Hao Hang¹, Gui-Lian Li¹, Xiu-Qin Zhao¹, Kang-Lin Wan¹, Li-Li Zhao¹

Affiliations

¹ National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, People's Republic of China.
² Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, People's Republic of China.
³ College of Life Science, Fujian Agriculture and Forestry University, Fuzhou, 350002, People's Republic of China.
⁴ Beijing Center for Disease Control and Prevention, Beijing, 100013, People's Republic of China.

^# Contributed equally.

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: embB; ethambutol; minimum inhibitory concentration; multidrug-resistant tuberculosis; mutations; ubiA.

Grants and funding

This study was supported by the projects from the National Key Research and Development Program of China (No. 2023YFC2307204), and National Key Program of Mega Infectious Diseases (Grant No. 2018ZX10302302). The funder had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation.