Modeling synergistic drug inhibition of Mycobacterium tuberculosis growth in murine macrophages
Modeling synergistic drug inhibition of Mycobacterium tuberculosis growth in murine macrophages
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DOI：
10.1039/c1mb05106g
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发表时间：
2011-01-01
影响因子：
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通讯作者：
Reifman, Jaques
中科院分区：
文献类型：
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作者：
Fang, Xin;Wallqvist, Anders;Reifman, Jaques
我们开发了一个基于代谢的系统生物学框架来模拟药物对小鼠巨噬细胞中结核分枝杆菌的生长抑制。我们用它模拟了3-硝基丙酸(3-NP)对细菌生长的体外抑制作用，并计算了相应的时间和药物浓度依赖的剂量-反应曲线。3-NP靶向乙醛分流中的异柠檬酸裂解酶1(ICL1)和ICL2酶，这是许多重要原核生物碳代谢的重要组成部分。我们使用该框架在电子模拟药物额外的酶与3-NP相结合，以了解如何在代谢酶目标之间产生协同作用。特别是，我们专注于探索中心碳代谢途径中的其他靶点，并确定联合抑制这些靶点和ICL1/ICL2酶的影响。因此，额外抑制乙醛酸分流中的苹果酸合成酶(MS)不会产生协同效应，而额外抑制3-甘油-3-磷酸脱氢酶(G3PD)显示出细菌生长的减少，超出了每种单一抑制所能达到的效果。ICL1/ICL2-MS对基本上作用于处理脂质的代谢途径中与碳源相同的分支(乙醛酸分流)，而ICL1/ICL2-G3PD对的抑制作用针对脂类利用途径中的不同分支。这使得ICL1/ICL2-G3PD药物组合能够协同抑制碳加工，并最终影响细胞生长。我们之前开发的体外条件下的模型未能捕捉到这些影响，强调了构建实验体外巨噬细胞系统的准确表示的重要性。
We developed a metabolism-based systems biology framework to model drug-induced growth inhibition of Mycobacterium tuberculosis in murine macrophage cells. We used it to simulate ex vivo bacterial growth inhibition due to 3-nitropropionate (3-NP) and calculated the corresponding time-and drug concentration-dependent dose-response curves. 3-NP targets the isocitrate lyase 1 (ICL1) and ICL2 enzymes in the glyoxylate shunt, an essential component in carbon metabolism of many important prokaryotic organisms. We used the framework to in silico mimic drugging additional enzymes in combination with 3-NP to understand how synergy can arise among metabolic enzyme targets. In particular, we focused on exploring additional targets among the central carbon metabolism pathways and ascertaining the impact of jointly inhibiting these targets and the ICL1/ICL2 enzymes. Thus, additionally inhibiting the malate synthase (MS) enzyme in the glyoxylate shunt did not produce synergistic effects, whereas additional inhibition of the glycerol-3-phosphate dehydrogenase (G3PD) enzyme showed a reduction in bacterial growth beyond what each single inhibition could achieve. Whereas the ICL1/ICL2-MS pair essentially works on the same branch of the metabolic pathway processing lipids as carbon sources (the glyoxylate shunt), the ICL1/ICL2-G3PD pair inhibition targets different branches among the lipid utilization pathways. This allowed the ICL1/ICL2-G3PD drug combination to synergistically inhibit carbon processing and ultimately affect cellular growth. Our previously developed model for in vitro conditions failed to capture these effects, highlighting the importance of constructing accurate representations of the experimental ex vivo macrophage system.