CWHM-974 is a fluphenazine derivative with improved antifungal activity againstCandida albicansdue to reduced susceptibility to multidrug transporter-mediated resistance mechanisms

Abstract

AbstractMultidrug resistance (MDR) transporters such as ATP Binding Cassette (ABC) and Major Facilitator Superfamily (MFS) 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 againstCandidaspp. compared to the fluphenazine and with activity againstCandidaspp. with reduced fluconazole susceptibility due to increased multidrug resistance transporters. Here, we show that the improvedC. albicansactivity is because fluphenazine induces its own resistance by triggering expression of 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 inC. albicansbut not inC. glabrata, despite inducingCDR1expression to high levels. Overall, CWHM-974 represents a unique example of a medicinal chemistry-based conversion of chemical scaffold from MDR-sensitive to MDR-resistant and, hence, active against fungi that have developed resistance to clinically used antifungals such as the azoles.