Altered Fatty Acid Metabolism Due to Rifampicin-Resistance Conferring Mutations in the rpoB Gene of Mycobacterium tuberculosis: Mapping the Potential of Pharmaco-metabolomics for Global Health and Personalized Medicine
Altered Fatty Acid Metabolism Due to Rifampicin-Resistance Conferring Mutations in the rpoB Gene of Mycobacterium tuberculosis: Mapping the Potential of Pharmaco-metabolomics for Global Health and Personalized Medicine
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DOI：
10.1089/omi.2012.0028
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发表时间：
2012-11-01
影响因子：
3.3
通讯作者：
Loots, Du Toit
中科院分区：
文献类型：
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作者：
du Preez, Ilse;Loots, Du Toit
我们通过比较两种 rpoB 突变型结核分枝杆菌菌株（S522L 和 S531L）与完全易感的野生型亲本菌株的脂肪酸代谢组，研究了使用气相色谱质谱 (GC-MS) 代谢组学来更好地表征利福平耐药性。使用生成的 GC-MS 代谢物数据，主成分分析 (PCA) 显示所有三个分析样品组之间存在明显差异。随后，我们使用 PCA 和偏最小二乘判别分析 (PLS-DA) 确定了对数据变化影响最大的代谢物。在利福平抗性突变体中检测到的代谢物标记物的改变表明各种10-甲基支链脂肪酸和细胞壁脂质的合成减少，并且短链脂肪酸作为碳源的使用增加。此外，之前报道的 rpoB S531L 突变体存在于超过 70% 的临床耐利福平结核分枝杆菌菌株中，与较少检测到的 rpoB S522L 突变体相比，rpoB S531L 突变体可能表现出更好的使用这些替代能源的能力。这项研究首次将结核分枝杆菌中的利福平耐药性、rpoB 突变和 RNA 聚合酶 β 亚基与脂肪酸代谢的改变联系起来，从而证明了药物代谢组学在识别与耐药性相关的新标记物方面可以发挥的作用。
We investigated the use of gas chromatography mass spectrometry (GC-MS) metabolomics to better characterize rifampicin-resistance by comparing the fatty acid metabolomes of two rpoB mutant Mycobacterium tuberculosis strains (S522L and S531L) to that of a fully susceptible wild-type parent strain. Using the generated GC-MS metabolite data, principal component analysis (PCA) showed a clear differentiation between all three sample groups analyzed. We subsequently identified those metabolites contributing most to the variation in the data using PCA and partial least squares discriminant analysis (PLS-DA). The altered metabolite markers detected in the rifampicin-resistant mutants indicate a decreased synthesis of various 10-methyl branched-chain fatty acids and cell wall lipids, and an increased use of the shorter-chain fatty acids as carbon sources. Furthermore, the rpoB S531L mutant, previously reported to occur in well over 70% of all clinical rifampicin-resistant M. tuberculosis strains, potentially showed a better capacity for using these alternative energy sources, compared to the less frequently detected rpoB S522L mutant. This study is the first of its kind to associate rifampicin resistance, rpoB mutations, and the beta-subunit of RNA polymerase in M. tuberculosis, with an altered fatty acid metabolism, thereby demonstrating the role that pharmaco-metabolomics can play in identifying new markers associated with drug resistance.