Rapamycin and caspofungin show synergistic antifungal effects in caspofungin-susceptible and caspofungin-resistant Candida strains in vitro

Abstract

ObjectivesCaspofungin is an echinocandin antifungal agent that inhibits synthesis of glucan required for the fungal cell wall. Resistance is mediated by mutation of Fks1 glucan synthase, among which S645P is the most common resistance-associated polymorphism. Rapamycin is a macrolide that inhibits the mechanistic target of rapamycin (mTOR) protein kinase activity. This study investigated the interaction between rapamycin and caspofungin in inhibiting the growth of wild type Candida albicans and Fks1 S645P mutant clinical isolate and wild type Candida lusitaniae and genetically engineered isogenic strain with Fks1 S645P mutation at equivalent position. MethodsInteractions between caspofungin and rapamycin were evaluated using the microdilution checkerboard method in liquid medium. The results were analysed using the fractional inhibitory concentration (FIC) index and the response surface (RS) analysis according to the Bliss model. ResultsSynergy between rapamycin and caspofungin was shown for C. albicans and C. lusitaniae strains by RS analysis of the checkerboard tests. Synergy was observed in strains sensitive and resistant to caspofungin. Weak subinhibitory concentrations of rapamycin were sufficient to restore caspofungin susceptibility. ConclusionsWe report here for the first time synergy between caspofungin and rapamycin in Candida species. Synergy was shown for strains susceptible and resistant to caspofungin. This study highlights the role of the TOR pathway in sensing antifungal-mediated cell wall stress and in modulating the cellular response to echinocandins in Candida yeasts.