PDF(Pubmed)
Abstract：
Multidrug resistance (MDR) transporters such as ATP-Binding Cassette (ABC) and Major Facilitator Superfamily proteins are important mediators of antifungal drug resistance, particularly with respect to azole class drugs. Consequently, identifying molecules that are not susceptible to this mechanism of resistance is an important goal for new antifungal drug discovery. As part of a project to optimize the antifungal activity of clinically used phenothiazines, we synthesized a fluphenazine derivative (CWHM-974) with 8-fold higher activity against Candida spp. compared to the fluphenazine and with activity against Candida spp. with reduced fluconazole susceptibility due to increased MDR transporters. Here, we show that the improved C. albicans activity is because fluphenazine induces its own resistance by triggering expression of Candida drug resistance (CDR) transporters while CWHM-974 induces expression but does not appear to be a substrate for the transporters or is insensitive to their effects through other mechanisms. We also found that fluphenazine and CWHM-974 are antagonistic with fluconazole in C. albicans but not in C. glabrata, despite inducing CDR1 expression to high levels. Overall, CWHM-974 is one of the few examples of a molecule in which relatively small structural modifications significantly reduced susceptibility to multidrug transporter-mediated resistance.
摘要：
多药耐药（MDR）转运蛋白，如ATP结合盒（ABC）和主要促进超家族蛋白是抗真菌药物耐药性的重要介质。特别是关于唑类药物。因此,鉴定对这种耐药机制不敏感的分子是发现新抗真菌药物的重要目标。作为优化临床使用的酚噻嗪的抗真菌活性项目的一部分，我们合成了对念珠菌的活性高8倍的氟奋乃静衍生物（CWHM-974）。与氟奋乃静相比，具有抗念珠菌的活性。由于MDR转运蛋白增加，氟康唑敏感性降低。这里,我们表明，白色念珠菌活性的改善是因为氟奋乃静通过触发念珠菌耐药（CDR）转运体的表达来诱导其自身的耐药性，而CWHM-974诱导表达，但似乎不是转运体的底物或对其作用不敏感通过其他机制。我们还发现氟奋乃静和CWHM-974在白色念珠菌中与氟康唑拮抗，但在光滑念珠菌中没有，尽管诱导CDR1表达到高水平。总的来说,CWHM-974是其中相对较小的结构修饰显着降低对多药转运蛋白介导的抗性的敏感性的分子的少数实例之一。
