Delayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism.
Delayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism.
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DOI：
10.1038/ncomms4369
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发表时间：
2014-02-26
影响因子：
16.6
通讯作者：
Bald, Dirk
中科院分区：
文献类型：
--
作者：
Koul, Anil;Vranckx, Luc;Dhar, Neeraj;Gohlmann, Hinrich W. H.;Oezdemir, Emre;Neefs, Jean-Marc;Schulz, Melanie;Lu, Ping;Mortz, Ejvind;McKinney, John D.;Andries, Koen;Bald, Dirk
Bedaquiline （BDQ）是一种ATP合成酶抑制剂，是几十年来首个被批准用于治疗耐多药结核病的药物。虽然BDQ在临床试验中表现出优异的疗效，但其在化疗第一周的早期杀菌活性很小。在这里，使用微流控装置和延时显微镜观察结核分枝杆菌，我们证实在暴露于BDQ的前3-4天没有明显的细菌溶解活性。bdq诱导的ATP合成抑制在药物加入后数小时内导致细菌抑制。转录和蛋白质组学分析表明，结核分枝杆菌对BDQ的反应是通过诱导休眠调节和激活atp生成途径，从而在初始药物暴露期间维持细菌活力。当分枝杆菌生长在脂质等不可发酵的能量源（阻碍糖酵解合成ATP）上时，bdq诱导的细菌杀伤能力显著增强。我们的研究结果表明，BDQ暴露会引发分枝杆菌的代谢重塑，从而使细菌短暂存活。抗结核抗生素贝达喹啉的杀菌活性延迟起效令人费解。在这里，Koul和他的同事使用多组学方法表明，这种药物触发了结核分枝杆菌的代谢重塑，使病原体能够短暂存活。
Bedaquiline (BDQ), an ATP synthase inhibitor, is the first drug to be approved for treatment of multidrug-resistant tuberculosis in decades. Though BDQ has shown excellent efficacy in clinical trials, its early bactericidal activity during the first week of chemotherapy is minimal. Here, using microfluidic devices and time-lapse microscopy of Mycobacterium tuberculosis, we confirm the absence of significant bacteriolytic activity during the first 3–4 days of exposure to BDQ. BDQ-induced inhibition of ATP synthesis leads to bacteriostasis within hours after drug addition. Transcriptional and proteomic analyses reveal that M. tuberculosis responds to BDQ by induction of the dormancy regulon and activation of ATP-generating pathways, thereby maintaining bacterial viability during initial drug exposure. BDQ-induced bacterial killing is significantly enhanced when the mycobacteria are grown on non-fermentable energy sources such as lipids (impeding ATP synthesis via glycolysis). Our results show that BDQ exposure triggers a metabolic remodelling in mycobacteria, thereby enabling transient bacterial survival. The delayed onset of bactericidal activity of the anti-tuberculosis antibiotic bedaquiline is puzzling. Here, Koul and colleagues show, using a multi-omics approach, that the drug triggers a metabolic remodelling in Mycobacterium tuberculosis that enables the pathogen’s transient survival.
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影响因子：
3.2
作者：
Beste, D. J. V.;Laing, E.;McFadden, J. J.
通讯作者：
McFadden, J. J.
结核分枝杆菌通用应激蛋白 Rv2623 通过 ATP 结合调节细菌生长：建立慢性持续感染的必要条件。
影响因子：
6.7
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Drumm JE;Mi K;Bilder P;Sun M;Lim J;Bielefeldt-Ohmann H;Basaraba R;So M;Zhu G;Tufariello JM;Izzo AA;Orme IM;Almo SC;Leyh TS;Chan J
通讯作者：
Chan J
影响因子：
64.8
作者：
Lee, Eun-Jin;Groisman, Eduardo A.
通讯作者：
Groisman, Eduardo A.
影响因子：
64.8
作者：
Galagan, James E.;Minch, Kyle;Peterson, Matthew;Lyubetskaya, Anna;Azizi, Elham;Sweet, Linsday;Gomes, Antonio;Rustad, Tige;Dolganov, Gregory;Glotova, Irina;Abeel, Thomas;Mahwinney, Chris;Kennedy, Adam D.;Allard, Rene;Brabant, William;Krueger, Andrew;Jaini, Suma;Honda, Brent;Yu, Wen-Han;Hickey, Mark J.;Zucker, Jeremy;Garay, Christopher;Weiner, Brian;Sisk, Peter;Stolte, Christian;Winkler, Jessica K.;Van de Peer, Yves;Iazzetti, Paul;Camacho, Diogo;Dreyfuss, Jonathan;Liu, Yang;Dorhoi, Anca;Mollenkopf, Hans-Joachim;Drogaris, Paul;Lamontagne, Julie;Zhou, Yiyong;Piquenot, Julie;Park, Sang Tae;Raman, Sahadevan;Kaufmann, Stefan H. E.;Mohney, Robert P.;Chelsky, Daniel;Moody, D. Branch;Sherman, David R.;Schoolnik, Gary K.
通讯作者：
Schoolnik, Gary K.
影响因子：
56.9
作者：
Andries, K;Verhasselt, P;Jarlier, V
通讯作者：
Jarlier, V