An in vivo platform for rapid high-throughput antitubercular drug discovery.
An in vivo platform for rapid high-throughput antitubercular drug discovery.
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DOI：
10.1016/j.celrep.2012.06.008
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发表时间：
2012-07-26
期刊：
影响因子：
8.8
通讯作者：
Ramakrishnan L
中科院分区：
文献类型：
--
作者：
Takaki K;Cosma CL;Troll MA;Ramakrishnan L
与其他传染病一样，结核病的治疗日益受到耐药性出现的阻碍。结合人类疾病复杂性的简易筛选工具将促进药物发现工作。海洋分枝杆菌感染的斑马鱼幼虫概括了结核病发病机制和药物治疗的关键方面。在这里，我们开发了这种模型，用于快速体内药物筛选，使用基于荧光的方法进行药物疗效和毒性的系列定量评估。我们提供了概念验证，即传统的细菌靶向抗结核药物以及新发现的宿主靶向药物将使用该模型发现。我们证明了该模型的实用性，用于识别抗菌药物的协同组合，并证明细菌和宿主靶向化合物之间的协同作用。因此，该平台可用于识别新的抗菌剂和全新类别的药物，通过靶向宿主途径来阻止感染。本研究开发的方法可广泛应用于其他感染性和非感染性疾病的小分子筛查。
Treatment of tuberculosis, like other infectious diseases, is increasingly hindered by the emergence of drug resistance. Drug discovery efforts would be facilitated by facile screening tools that incorporate the complexities of human disease. Mycobacterium marinum-infected zebrafish larvae recapitulate key aspects of tuberculosis pathogenesis and drug treatment. Here we develop this model for rapid in vivo drug screening using fluorescence-based methods for serial quantitative assessment of drug efficacy and toxicity. We provide proof-of-concept that both traditional bacterial-targeting antitubercular drugs as well as newly identified host-targeting drugs would be discovered using this model. We demonstrate the model’s utility for identification of synergistic combinations of antibacterial drugs and demonstrate synergy between bacterial and host targeting compounds. Thus the platform can be used to identify new antibacterial agents and entirely new classes of drugs that thwart infection by targeting host pathways. The methods developed here should be widely applicable to small molecule screens for other infectious and noninfectious diseases.
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影响因子：
14.8
作者：
Laggner, Christian;Kokel, David;Setola, Vincent;Tolia, Alexandra;Lin, Henry;Irwin, John J.;Keiser, Michael J.;Cheung, Chung Yan J.;Minor, Daniel L., Jr.;Roth, Bryan L.;Peterson, Randall T.;Shoichet, Brian K.
通讯作者：
Shoichet, Brian K.
DOI：
10.1084/jem.20080767
发表时间：
2008-11-24
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chen M;Divangahi M;Gan H;Shin DS;Hong S;Lee DM;Serhan CN;Behar SM;Remold HG
通讯作者：
Remold HG
影响因子：
3.7
作者：
Das BC;McCartin K;Liu TC;Peterson RT;Evans T
通讯作者：
Evans T
DOI：
10.1164/rccm.200210-1125oc
发表时间：
2003-05-15
影响因子：
24.7
作者：
Jindani, A;Doré, CJ;Mitchison, DA
通讯作者：
Mitchison, DA
影响因子：
64.5
作者：
Kumar, Dhiraj;Nath, Lekha;Rao, Kanury V. S.
通讯作者：
Rao, Kanury V. S.