Key Laboratory of Major Diseases in Children, Ministry of Education, National Key Discipline of Pediatrics (Capital Medical University), Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Clinical Research Center for Respiratory Diseases, National Center for Children's Health, Beijing, China.
National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory for Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, China.
Infect Genet Evol. 2019 Aug;72:151-158. doi: 10.1016/j.meegid.2018.09.027. Epub 2018 Oct 4.
Selective pressure from antibiotic use is one of the most important risk factors associated with the development of drug resistance in Mycobacterium tuberculosis (MTB). However, the mechanisms underlying drug resistance at the molecular level remain partly unclear. Therefore, the purpose of this study was to investigate the potential functional effect of novel mutations arising from anti-tuberculosis treatment. We analyzed two multidrug-resistant TB (MDR-TB) isolates from the same patient; one collected before and one almost a year after commencing MDR-TB treatment. The post-treatment isolate exhibited elevated ethambutol resistance. We sequenced the whole genomes of the two clinical isolates and detected six novel polymorphisms affecting the genes Rv1026, nc0021, Rv2155c, Rv2437, and Rv3696c, and the intergenic region between Rv2764c and Rv2765. Metabolomics approach was used to reveal the effect of the found variation on the metabolic pathways of MTB. Partial least squares-discriminant analysis showed a clear differentiation between the two isolates, involving a total of 175 metabolites. Pathway analysis showed that these metabolites are mainly involved in amino sugar and nucleotide sugar metabolism, β-alanine metabolism, sulfur metabolism, and galactose metabolism. The increased ethambutol resistance exhibited by the post-treatment MDR-TB strain could speculatively be linked to the identified genetic variations, which affected the synthesis of a number of metabolites associated with sources of carbon and energy. This may have been the main factor underlying the increased ethambutol resistance of this isolate.
抗生素的选择压力是导致结核分枝杆菌（MTB）耐药性发展的最重要危险因素之一。然而，耐药性在分子水平上的机制仍部分不清楚。因此，本研究的目的是研究抗结核治疗引起的新突变的潜在功能影响。我们分析了来自同一患者的两个耐多药结核（MDR-TB）分离株；一个在开始 MDR-TB 治疗之前收集，另一个几乎在治疗一年后收集。治疗后分离株表现出较高的乙胺丁醇耐药性。我们对两个临床分离株的全基因组进行测序，检测到 6 个影响基因 Rv1026、nc0021、Rv2155c、Rv2437 和 Rv3696c 以及 Rv2764c 和 Rv2765 之间基因间区的新多态性。代谢组学方法用于揭示发现的变异对 MTB 代谢途径的影响。偏最小二乘判别分析显示两个分离株之间存在明显差异，涉及总共 175 种代谢物。途径分析表明，这些代谢物主要涉及氨基糖和核苷酸糖代谢、β-丙氨酸代谢、硫代谢和半乳糖代谢。治疗后 MDR-TB 菌株表现出的增加的乙胺丁醇耐药性可能与鉴定的遗传变异有关，这些变异影响了与碳和能源来源相关的许多代谢物的合成。这可能是该分离株乙胺丁醇耐药性增加的主要因素。
