Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
Cell Rep. 2012 Jul 26;2(1):175-84. doi: 10.1016/j.celrep.2012.06.008. Epub 2012 Jul 20.
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 a 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 and newly identified host-targeting drugs would be discovered through the use of this model. We demonstrate the model's utility for the 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.
结核病的治疗，与其他传染病一样，越来越受到耐药性出现的阻碍。如果有简便的筛选工具能够整合人类疾病的复杂性，将有助于药物的发现。感染结核分枝杆菌的斑马鱼幼虫可重现结核病发病机制和药物治疗的关键方面。在这里，我们使用基于荧光的方法开发了一种快速体内药物筛选模型，用于对药物疗效和毒性进行连续定量评估。我们提供了一个概念验证，证明通过使用该模型可以发现传统的针对细菌的抗结核药物和新发现的针对宿主的药物。我们证明了该模型在鉴定抗菌药物协同组合方面的实用性，并证明了细菌和宿主靶向化合物之间的协同作用。因此，该平台可用于鉴定通过靶向宿主途径来抵御感染的新型抗菌药物和全新类别的药物。这里开发的方法应该广泛适用于针对其他传染性和非传染性疾病的小分子筛选。
