Saquinavir potentiates itraconazole's antifungal activity against multidrug-resistant Candida auris in vitro and in vivo.

Abstract

Candida species are highly opportunistic yeasts that are responsible for serious invasive fungal infections among immunocompromised patients worldwide. Due to the increase of drug resistance and incidence of infections, there is an urgent need to develop new antifungals and to identify co-drugs that can sensitize drug-resistant Candida to antifungals. The objective of this study was to assess the effect of saquinavir on the activity of azole antifungals against Candida auris. The in vitro interaction of saquinavir and three azole antifungals (itraconazole, voriconazole and fluconazole) was evaluated against a panel of C. auris isolates. The itraconazole/saquinavir combination exhibited a synergistic relationship against all C. auris isolates tested with the fractional inhibitory concentration index (FICI) ranging from 0.03 to 0.27. Moreover, a time-kill kinetics assay revealed that saquinavir restored the itraconazole's fungistatic activity against C. auris. Furthermore, saquinavir restored itraconazole's antifungal activity against other clinically important Candida species. The mechanistic investigation indicated that saquinavir significantly inhibited efflux pumps, glucose utilization and ATP synthesis in Candida. Finally, a murine model of C. auris infection was used to evaluate the efficacy of the itraconazole/saquinavir combination in the presence of ritonavir (as a pharmacokinetic enhancer). The combination significantly reduced the fungal burden in the kidneys by 0.93-log10 colony forming units (88%) compared to itraconazole alone. This study identified that saquinavir exhibits a potent synergistic relationship in combination with itraconazole against Candida species, which warrants further consideration.