1. Longyan First Affiliated Hospital of Fujian Medical University, Longyan Fujian 364000, China; 2. Longyan People Hospital, Longyan Fujian 364000, China
Study on Mutation and Its Characteristics of Mycobacterium Tuberculosis Multidrug Resistance Genes Based on Whole-genome Sequencing
1. Longyan First Affiliated Hospital of Fujian Medical University, Longyan Fujian 364000, China; 2. Longyan People Hospital, Longyan Fujian 364000, China
摘要Objective: The increase in the development of resistance to multiple drugs in mycobacterium tuberculosis(MTB) poses a substantial obstacle to the prevention and management of tuberculosis(TB). A thorough investigation of the genotypes linked to multidrug resistance is crucial for comprehending the mechanisms underlying drug resistance. The objective of this research was to assess the attributes of gene mutations associated with multidrug resistance in clinical isolates of mycobacterium tuberculosis through the utilization of whole-genome sequencing. Methods: A total of 124 strains of drug-resistant mycobacterium tuberculosis were collected, and the genomic DNA of both multidrug-resistant and rifampin-resistant strains were extracted and sequenced. Bioinformatics was used to analyze and compare multidrug resistance-related gene sequences in order to detect the variation of multidrug resistance genes. Results: The results revealed that the resistance spectrum of XDR-TB group was much wider than that of the other three groups, with the RR-TB group having the most limited resistance spectrum. Within the MDR-TB strains, fabG1 exhibited the highest frequency of mutations, while RRS, gyrA, and rpoB were identified as the predominant mutation bases in XDR-TB strains. Additionally, rpoB emerged as the primary mutation base in MDR-TB and RR-TB strains. Notably, the fabG1 mutation was found to be closely associated with PDR-TB. Furthermore, the correlation between the mutation rate of rpoB and multidrug resistance was deemed to be of secondary importance. Conclusion: Various strains of MTB exhibited distinct mechanisms of drug resistance, with the gene mutations of fabG1, RRS, gyrA, and rpoB potentially playing a pivotal role in the development of drug resistance. However, the primary genes responsible for drug resistance mutations varied among different strains of TB.
Abstract：Objective: The increase in the development of resistance to multiple drugs in mycobacterium tuberculosis(MTB) poses a substantial obstacle to the prevention and management of tuberculosis(TB). A thorough investigation of the genotypes linked to multidrug resistance is crucial for comprehending the mechanisms underlying drug resistance. The objective of this research was to assess the attributes of gene mutations associated with multidrug resistance in clinical isolates of mycobacterium tuberculosis through the utilization of whole-genome sequencing. Methods: A total of 124 strains of drug-resistant mycobacterium tuberculosis were collected, and the genomic DNA of both multidrug-resistant and rifampin-resistant strains were extracted and sequenced. Bioinformatics was used to analyze and compare multidrug resistance-related gene sequences in order to detect the variation of multidrug resistance genes. Results: The results revealed that the resistance spectrum of XDR-TB group was much wider than that of the other three groups, with the RR-TB group having the most limited resistance spectrum. Within the MDR-TB strains, fabG1 exhibited the highest frequency of mutations, while RRS, gyrA, and rpoB were identified as the predominant mutation bases in XDR-TB strains. Additionally, rpoB emerged as the primary mutation base in MDR-TB and RR-TB strains. Notably, the fabG1 mutation was found to be closely associated with PDR-TB. Furthermore, the correlation between the mutation rate of rpoB and multidrug resistance was deemed to be of secondary importance. Conclusion: Various strains of MTB exhibited distinct mechanisms of drug resistance, with the gene mutations of fabG1, RRS, gyrA, and rpoB potentially playing a pivotal role in the development of drug resistance. However, the primary genes responsible for drug resistance mutations varied among different strains of TB.
通讯作者:
QUE Qun-feng. E-mail: qqf15395978337@163.com
引用本文:
HUANG Hao-nan, QIU Qun-feng, CHEN Yan-hong, ZHANG Chun-chun. Study on Mutation and Its Characteristics of Mycobacterium Tuberculosis Multidrug Resistance Genes Based on Whole-genome Sequencing[J]. 中国生物医学工程学报(英文版）, 2023, 32(4): 145-153.
HUANG Hao-nan, QIU Qun-feng, CHEN Yan-hong, ZHANG Chun-chun. Study on Mutation and Its Characteristics of Mycobacterium Tuberculosis Multidrug Resistance Genes Based on Whole-genome Sequencing. Chinese Journal of Biomedical Engineering, 2023, 32(4): 145-153.
[1] Seloma Nm, Makgatho ME, Maimela E.Knowledge, attitude and preventative practice of tuberculosis in rural communities of Dikgale, Mamabolo and Mothiba health and demographic surveillance system in Limpopo province, South Africa[J]. BMC Public Health, 2023, 23(1): 1687. [2] Romagnoli A, Di Rienzo M, Petruccioli E, et al.The ubiquitin ligase TRIM32 promotes theautophagic response to Mycobacterium tuberculosis infection in macrophages[J]. Cell Death Dis, 2023,14(8):505. [3] Liu Ting, Xiao Yuanyuan.World Health Organization:Global priority research agenda for antimicrobial resistance in human health[J]. Chinese Journal of Infection Control, 2023, 22(08): 995-998. (刘婷, 肖园园. 世界卫生组织人类健康中抗微生物药物耐药性的全球优先研究议题[J]. 中国感染控制杂志,2023,22(08):995-998.) [4] Wang Shaohua, Chen Ruiqin, Chang Wenjing.Drug resistance of Mycobacterium tuberculosis in five monitoring sites of Henan Province,2013-2018[J].Chinese Journal of Infection Control,2023,22(06):629-636. (王少华, 陈瑞琴, 常文静,等. 2013-2018年河南省5个耐药监测点结核分枝杆菌耐药性[J]. 中国感染控制杂志,2023,22(06):629-636.) [5] Hu T, Chitnis N, Monos D, et al.Next-generation sequencing technologies: An overview[J]. Hum Immunol, 2021,82(11):801-811. [6] Wang D, Cheng J, Peng L, et al.Comparison of metagenomic second- and third-generation sequencing by diagnostic sensitivity and specificity in tuberculosis patients[J]. Clin Lab, 2023,69(9):37702690. [7] Ghodousi A, Darban-Sarokhalil D, Shahraki AH, et al.Editorial: Genomics-based strategies for advanced drug resistance and epidemiological surveillance of Mycobacterium tuberculosis and other non-tuberculous mycobacteria[J]. Front Microbiol, 2023,14:1264285. [8] Jagielski T, Brzostek A, van Belkum A, et al. A close-up on the epidemiology and transmission of multidrug-resistant tuberculosis in Poland[J]. Eur J Clin Microbiol Infect Dis, 2015,34(1):41-53. [9] Suresh M, Nithya N, Jayasree PR, et al.Mutational analyses of regulatory genes, mexR, nalC, nalD and mexZ of mexAB-oprM and mexXY operons, in efflux pump hyperexpressing multidrug-resistant clinical isolates of Pseudomonas aeruginosa[J]. World J Microbiol Biotechnol, 2018,34(6):83. [10] Mahmood N, Abbas SN, Faraz N, et al.Mutational analysis of gyrB at amino acids: G481A & D505A in multidrug resistant (MDR) tuberculosis patients[J]. J Infect Public Health, 2019,12(4):496-501. [11] Pervez MT, Hasnain M, Abbas SH, et al.A Comprehensive review of performance of next-generation sequencing platforms[J]. Biomed Res Int, 2022,2022:3457806. [12] Abdelrahman MA, Almahli H, Al-Warhi T, et al.Development of novel Isatin-Tethered quinolines as anti-tubercular agents against multi and extensively drug-resistant Mycobacterium tuberculosis[J]. Molecules, 2022,27(24):8807. [13] Trisakul K, Nonghanphithak D, Chaiyachat P, et al.High clustering rate and genotypic drug-susceptibility screening for the newly recommended anti-tuberculosis drugs among global extensively drug-resistant Mycobacterium tuberculosis isolates[J]. Emerg Microbes Infect, 2022,11(1):1857-1866. [14] Verma AK, Yadav RN, Kumar G, et al.Multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis strains in geriatrics: An analysis and its implications in tuberculosis control[J]. J Clin Tuberc Other Mycobact Dis, 2022,27:100317. [15] Tiberi S, Utjesanovic N, Galvin J, et al.Drug resistant TB-latest developments in epidemiology, diagnostics and management[J]. Int J Infect Dis, 2022,124(1):20-25. [16] Jin Shenghua, Liu Xuejun, Zhang Li.The application of noise characteristics of primary Affymetrix genechip(R) data[J]. Chinese Journal of Biomedical Engineering, 2011,30(3):382-387. (金圣华, 刘学军, 张礼. Affymetrix基因芯片原始数据噪声分析与应用[J]. 中国生物医学工程学报,2011,30(3):382-387.) [17] Ma Ning, Zhang Zhengguo.A gene selection method based on GO annotations[J]. Chinese Journal of Biomedical Engineering, 2009,28(5):696-700,706. (马宁, 张正国. 一种基于Gene Ontology注释信息的基因选择算[J]. 中国生物医学工程学报,2009,28(5):696-700, 706.) [18] Jabbar A PJE, DE Sessions PF, et al.Whole genome sequencing of drug resistant Mycobacterium tuberculosis isolates from a high burden tuberculosis region of North West Paki[J]. Sci Rep, 2019,9:14996. [19] Levy SE, Boone BE.Next-generation sequencing strategies[J]. Cold Spring Harb Perspect Med, 2019,9(7):025791. [20] Dorado G, Gálvez S, Rosales TE, et al.Analyzing modern biomolecules: The revolution of nucleic-acid sequencing - review[J]. Biomolecules, 2021,11(8):1111. [21] Ebert P, Audano PA, Zhu Q, et al.Haplotype-resolved diverse human genomes and integrated analysis of structural variation[J]. Science, 2021,372(6537):7117. [22] Fan X, Yang C, Li W, et al.SMOOTH-seq: single-cell genome sequencing of human cells on a third-generation sequencing platform[J]. Genome Biol, 2021,22(1):195. [23] Wang L, Yang J, Chen L, et al.Whole-genome sequencing of Mycobacterium tuberculosis for prediction of drug resistance[J]. Epidemiol Infect, 2022,150:22. [24] Song WM, Li SJ, Liu JY, et al.Impact of alcohol drinking and tobacco smoking on the drug-resistance of newly diagnosed tuberculosis: a retrospective cohort study in Shandong, China, during 2004-2020[J]. BMJ Open, 2022,12(7):59149. [25] Rudeeaneksin J, Phetsuksiri B, Nakajima C, et al.Drug-resistant Mycobacterium tuberculosis and its genotypes isolated from an outbreak in western Thailand[J]. Trans R Soc Trop Med Hyg, 2021,115(8):886-895. [26] Ortakoylu MG, Kibar Akilli I, Kilic L, et al.Management of polydrug-resistant tuberculosis[J]. Medicina (Kaunas), 2023,59(2):246. [27] Jain B, Kulkarni S.Development of DNA bio-chip for detection of mutations of rpoB, embB and inhA genes in drug-resistant Mycobacterium tuberculosis[J]. Indian J Clin Biochem, 2023,38(2):242-250. [28] Pinhata J, Brandao AP, Mendes FF, et al.Correlating genetic mutations with isoniazid phenotypic levels of resistance in Mycobacterium tuberculosis isolates from patients with drug-resistant tuberculosis in a high burden setting[J]. Eur J Clin Microbiol Infect Dis, 2021,40(12):2551-2561. [29] Brown TS, Eldholm V, Brynildsrud O, et al.Evolution and emergence of multidrug-resistant Mycobacterium tuberculosis in Chisinau, Moldova[J]. Microb Genom, 2021,7(8):000620. [30] Bai-lan XU. Role of miRNA-27a in regulating the immune function of pulmonary tuberculosis rat model[J]. Chinese Journal of Biomedical Engineering, 2022,31(3):112-119, 138.
