Zilbermintz Leeor, Leonardi William, Jeong Sun-Young, Sjodt Megan, McComb Ryan, Ho Chi-Lee C, Retterer Cary, Gharaibeh Dima, Zamani Rouzbeh, Soloveva Veronica, Bavari Sina, Levitin Anastasia, West Joel, Bradley Kenneth A, Clubb Robert T, Cohen Stanley N, Gupta Vivek, Martchenko Mikhail
Keck Graduate Institute, Claremont, CA 91711.
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305.
Sci Rep. 2015 Aug 27;5:13476. doi: 10.1038/srep13476.
A longstanding and still-increasing threat to the effective treatment of infectious diseases is resistance to antimicrobial countermeasures. Potentially, the targeting of host proteins and pathways essential for the detrimental effects of pathogens offers an approach that may discover broad-spectrum anti-pathogen countermeasures and circumvent the effects of pathogen mutations leading to resistance. Here we report implementation of a strategy for discovering broad-spectrum host-oriented therapies against multiple pathogenic agents by multiplex screening of drugs for protection against the detrimental effects of multiple pathogens, identification of host cell pathways inhibited by the drug, and screening for effects of the agent on other pathogens exploiting the same pathway. We show that a clinically used antimalarial drug, Amodiaquine, discovered by this strategy, protects host cells against infection by multiple toxins and viruses by inhibiting host cathepsin B. Our results reveal the practicality of discovering broadly acting anti-pathogen countermeasures that target host proteins exploited by pathogens.
对抗菌对策产生耐药性是长期以来且仍在加剧的对传染病有效治疗的威胁。从潜在意义上讲，针对病原体有害作用所必需的宿主蛋白和途径进行靶向治疗，提供了一种可能发现广谱抗病原体对策并规避病原体突变导致耐药性影响的方法。在此，我们报告了一种策略的实施情况，该策略通过对药物进行多重筛选以保护宿主免受多种病原体的有害影响、鉴定药物抑制的宿主细胞途径以及筛选该药物对利用相同途径的其他病原体的影响，来发现针对多种病原体的广谱宿主导向疗法。我们表明，通过该策略发现的一种临床使用的抗疟药物阿莫地喹，通过抑制宿主组织蛋白酶B来保护宿主细胞免受多种毒素和病毒的感染。我们的结果揭示了发现针对病原体所利用的宿主蛋白的广泛作用的抗病原体对策的实用性。
