The lack of rapid and efficient diagnostics impedes largely the epidemic control of multidrug-resistant tuberculosis, and might misguide the therapeutic strategies as well. This study aimed to identify novel multidrug-resistant tuberculosis biomarkers to improve the early intervention, symptomatic treatment and control of the prevalence of multidrug-resistant tuberculosis. The serum small molecule metabolites in healthy controls, patients with drug-susceptible tuberculosis, and patients with multidrug-resistant tuberculosis were screened using ultra-high-performance liquid chromatography combined with quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS). The differentially abundant metabolites were filtered out through multidimensional statistical analysis and bioinformatics analysis. Compared with drug-susceptible tuberculosis patients and healthy controls, the levels of 13 metabolites in multidrug-resistant tuberculosis patients altered. Among them, the most significant changes were found in N1-Methyl-2-pyridone-5-carboxamide (N1M2P5C), 1-Myristoyl-sn-glycerol-3-phosphocholine (MG3P), Caprylic acid (CA), and D-Xylulose (DX). And a multidrug-resistant tuberculosis/drug-susceptible tuberculosis differential diagnostic model was built based on these four metabolites, achieved the accuracy, sensitivity, and specificity of 0.928, 86.7%, and 86.7%, respectively. The enrichment analysis of metabolic pathways showed that the phospholipid remodeling of cell membranes was active in multidrug-resistant tuberculosis patients. In addition, in patients with tuberculosis, the metabolites of dipalmitoyl phosphatidylcholine (DPPC), a major component of pulmonary surfactant, were down-regulated. N1M2P5C, MG3P, CA, and DX may have the potential to serve as novel multidrug-resistant tuberculosis biomarkers. This research provides a preliminary experimental basis to further investigate potential multidrug-resistant tuberculosis biomarkers.

Impact statement

The MDR-TB incidence remains high, making the effective control of TB epidemic yet challenging. Rapid and accurate diagnosis is vitally important for improving the therapeutic efficacy and controlling the prevalence of drug resistance TB. Metabolomics has dramatic potential to distinguish MDR-TB and DS-TB. N1M2P5C, MG3P, CA, and DX that we identified in this study might have potential as novel MDR-TB biomarkers. The phospholipid remodeling of cell membranes was highly active in MDR-TB. The DPPC metabolites in TB were significantly down-regulated. This work aimed to investigate potential MDR-TB biomarkers to enhance the clinical diagnostic efficacy. The metabolic pathway distinctly altered in MDR-TB might provide novel targets to develop new anti-TB drugs.

中文翻译：

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使用UPLC-Q-TOF-MS的新型耐药结核病生物标记物。

缺乏快速有效的诊断方法在很大程度上阻碍了耐多药结核病的流行控制，并且也可能误导了治疗策略。这项研究旨在鉴定新型的耐多药结核病生物标记物，以改善多药耐性结核病的早期干预，对症治疗和控制。使用超高效液相色谱结合四极杆飞行时间质谱（UPLC-Q-TOF）筛选健康对照，药物敏感型结核病患者和多药耐药性结核病患者的血清小分子代谢物-多发性硬化症）。通过多维统计分析和生物信息学分析将差异丰富的代谢物滤出。与药物敏感性结核病患者和健康对照组相比，耐多药结核病患者的13种代谢产物水平发生了变化。其中最显着的变化是N1-甲基-2-吡啶酮-5-羧酰胺（N1M2P5C），1-肉豆蔻酰基-sn-甘油-3-磷酸胆碱（MG3P），辛酸（CA）和D-木酮糖（DX）。基于这四种代谢物建立了耐多药结核/药物敏感性结核鉴别诊断模型，其准确度，灵敏度和特异性分别为0.928、86.7％和86.7％。代谢途径的富集分析表明，在多药耐药结核病患者中，细胞膜的磷脂重塑很活跃。此外，在结核病患者中，二棕榈酰磷脂酰胆碱（DPPC）的代谢产物 肺表面活性剂的主要成分被下调。N1M2P5C，MG3P，CA和DX可能具有作为新型耐多药结核病生物标记物的潜力。该研究为进一步研究潜在的耐多药结核病生物标志物提供了初步的实验基础。

影响陈述

耐多药结核病的发病率仍然很高，因此有效控制结核病流行仍具有挑战性。快速准确的诊断对于提高治疗效果和控制耐药结核的流行至关重要。代谢组学具有区分MDR-TB和DS-TB的巨大潜力。我们在这项研究中确定的N1M2P5C，MG3P，CA和DX可能具有作为新型MDR-TB生物标志物的潜力。细胞膜的磷脂重塑在耐多药结核病中具有很高的活性。TB中的DPPC代谢产物显着下调。这项工作旨在研究潜在的耐多药结核病生物标志物，以增强临床诊断功效。在耐多药结核病中明显改变的代谢途径可能为开发新的抗结核药物提供新的靶标。