Synergistic interactions of sulfamethoxazole and azole antifungal drugs against emerging multidrug-resistant Candida auris

•Sulfamethoxazole (SMX) showed potent synergy with fluconazole against Candida auris.•Combination with newer azole drugs enhanced and broadened the spectrum of activity.•SMX–voriconazole displayed potent in vivo activity in a Caenorhabditis elegans infection model.•The mechanism of synergy was mediated by interference with the fungal folate pathway.•Mechanisms of azole resistance significantly impacted the synergistic relationship. Candida auris is an emerging multidrug-resistant pathogen implicated in numerous outbreaks worldwide, with a notably high mortality rate (ca. 60%). A significant challenge with treatment of these infections is the resistance of C. auris to most antifungal drugs used clinically. Thus, finding co-drugs capable of overcoming resistance to frontline antifungals is of prime clinical importance. In this study, the ability of the combination of different sulfa drugs with azole antifungals to inhibit the growth of azole-resistant C. auris isolates was evaluated. Among the active sulfa drugs, sulfamethoxazole exhibited the most potent in vitro synergistic interactions with voriconazole and itraconazole. The sulfamethoxazole–voriconazole combination restored voriconazole's fungistatic activity against three of eight voriconazole-resistant clinical isolates. Similarly, the sulfamethoxazole–itraconazole combination restored itraconazole's fungistatic activity against three of four itraconazole-resistant clinical isolates. This activity was further confirmed in vivo in a Caenorhabditis elegans model of C. auris infection. The sulfamethoxazole–voriconazole combination enhanced survival of nematodes infected with C. auris by nearly 70%. Notably, these data indicate that the efficacy of this novel combination is dependent on the underlying mechanism of azole resistance. Mutant strains demonstrating azole resistance by either overproduction of or decreased affinity for the azole target (ERG11p) were found highly to be susceptible to the sulfamethoxazole–azole combination. However, this synergistic interaction was ineffective against mutant strains that demonstrated azole resistance via efflux pump hyperactivity. In conclusion, sulfamethoxazole represents a promising co-drug that can restore the efficacy of certain azole antifungal drugs against some azole-resistant isolates of C. auris.