Bedaquiline reprograms central metabolism to reveal glycolytic vulnerability in Mycobacterium tuberculosis.
Bedaquiline reprograms central metabolism to reveal glycolytic vulnerability in Mycobacterium tuberculosis.
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DOI：
10.1038/s41467-020-19959-4
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发表时间：
2020-11-30
影响因子：
16.6
通讯作者：
Steyn AJC
中科院分区：
文献类型：
--
作者：
Mackenzie JS;Lamprecht DA;Asmal R;Adamson JH;Borah K;Beste DJV;Lee BS;Pethe K;Rousseau S;Krieger I;Sacchettini JC;Glasgow JN;Steyn AJC
贝达奎兰(BDQ)被批准用于结核病的治疗引起了人们对抑制能量代谢作为一种治疗范例的浓厚兴趣。然而，目前还不清楚BDQ是如何触发结核分枝杆菌(Mtb)细胞死亡的。利用13C同位素分析，我们发现BDQ处理的Mtb重定向了中心碳代谢，诱导了易受糖酵解和糖异生遗传干扰的代谢脆弱状态。代谢通量谱表明，BDQ处理的Mtb依赖于糖酵解来产生ATP，通过乙醛分流增加通量来运行一个分叉的TCA循环，并且需要无性交和柠檬酸甲酯循环的酶。以BDQ为靶点的氧化磷酸化(OXPHOS)，同时通过糖酵解的遗传干扰抑制底物水平的磷酸化，导致快速绝育。我们的发现为BDQ诱导细胞死亡的代谢机制提供了洞察力，并为开发针对OXPHOS和糖酵解的联合疗法建立了一个范例。贝达奎林(BDQ)是一种已知的结核病治疗方法，但细胞死亡的确切机制尚不清楚。在这里，作者探索了BDQ治疗下结核分枝杆菌的代谢特征，并发现当氧化磷酸化也是靶点时，依赖于糖酵解和协同细胞死亡。
The approval of bedaquiline (BDQ) for the treatment of tuberculosis has generated substantial interest in inhibiting energy metabolism as a therapeutic paradigm. However, it is not known precisely how BDQ triggers cell death in Mycobacterium tuberculosis (Mtb). Using 13C isotopomer analysis, we show that BDQ-treated Mtb redirects central carbon metabolism to induce a metabolically vulnerable state susceptible to genetic disruption of glycolysis and gluconeogenesis. Metabolic flux profiles indicate that BDQ-treated Mtb is dependent on glycolysis for ATP production, operates a bifurcated TCA cycle by increasing flux through the glyoxylate shunt, and requires enzymes of the anaplerotic node and methylcitrate cycle. Targeting oxidative phosphorylation (OXPHOS) with BDQ and simultaneously inhibiting substrate level phosphorylation via genetic disruption of glycolysis leads to rapid sterilization. Our findings provide insight into the metabolic mechanism of BDQ-induced cell death and establish a paradigm for the development of combination therapies that target OXPHOS and glycolysis. Bedaquiline (BDQ) is a known tuberculosis treatment, but the precise mechanism of cell death is unclear. Here, the authors explore the metabolic profiles of M. tuberculosis upon BDQ treatment and find reliance on glycolysis and synergistic cell death when oxidative phosphorylation is also targeted.
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影响因子：
--
作者：
Beste DJ;Nöh K;Niedenführ S;Mendum TA;Hawkins ND;Ward JL;Beale MH;Wiechert W;McFadden J
通讯作者：
McFadden J
影响因子：
2.8
作者：
Gengenbacher, Martin;Rao, Srinivasa P. S.;Dick, Thomas
通讯作者：
Dick, Thomas
影响因子：
6.7
作者：
Beste DJ;Bonde B;Hawkins N;Ward JL;Beale MH;Noack S;Nöh K;Kruger NJ;Ratcliffe RG;McFadden J
通讯作者：
McFadden J
影响因子：
6.4
作者：
Bald D;Villellas C;Lu P;Koul A
通讯作者：
Koul A
影响因子：
7.7
作者：
Cumming BM;Addicott KW;Adamson JH;Steyn AJ
通讯作者：
Steyn AJ