Holmes Ann R, Cardno Tony S, Strouse J Jacob, Ivnitski-Steele Irena, Keniya Mikhail V, Lackovic Kurt, Monk Brian C, Sklar Larry A, Cannon Richard D
Sir John Walsh Research Institute, University of Otago Faculty of Dentistry, PO Box 647, Dunedin 9054, New Zealand.
Department of Biochemistry, University of Otago, PO Box 56, Dunedin 9054, New Zealand.
Future Med Chem. 2016 Aug;8(12):1485-501. doi: 10.4155/fmc-2016-0050. Epub 2016 Jul 27.
Resistance to antifungal drugs is an increasingly significant clinical problem. The most common antifungal resistance encountered is efflux pump-mediated resistance of Candida species to azole drugs. One approach to overcome this resistance is to inhibit the pumps and chemosensitize resistant strains to azole drugs. Drug discovery targeting fungal efflux pumps could thus result in the development of azole-enhancing combination therapy. Heterologous expression of fungal efflux pumps in Saccharomyces cerevisiae provides a versatile system for screening for pump inhibitors. Fungal efflux pumps transport a range of xenobiotics including fluorescent compounds. This enables the use of fluorescence-based detection, as well as growth inhibition assays, in screens to discover compounds targeting efflux-mediated antifungal drug resistance. A variety of medium- and high-throughput screens have been used to identify a number of chemical entities that inhibit fungal efflux pumps.
对抗真菌药物的耐药性是一个日益严重的临床问题。最常见的抗真菌耐药性是念珠菌属通过外排泵介导对唑类药物产生的耐药性。克服这种耐药性的一种方法是抑制这些泵，并使耐药菌株对唑类药物产生化学敏感性。因此，针对真菌外排泵进行药物研发可能会促成唑类增强联合疗法的发展。在酿酒酵母中对真菌外排泵进行异源表达，为筛选泵抑制剂提供了一个通用系统。真菌外排泵可转运包括荧光化合物在内的一系列外源性物质。这使得在筛选过程中能够使用基于荧光的检测方法以及生长抑制试验，以发现针对外排介导的抗真菌药物耐药性的化合物。已经使用了各种中高通量筛选方法来鉴定一些抑制真菌外排泵的化学实体。
