Invasive candidiasis presents an emerging global public health challenge due to the emergence of resistance to the frontline treatment options, such as fluconazole. Hence, the identification of other compounds capable of pairing with fluconazole and averting azole-resistance would potentially prolong the clinical utility of this important group. In an effort to repurpose drugs in the field of antifungal drug discovery, we explored sulfa antibacterial drugs for the purpose of reverting azole resistance in Candida. In this study, we assembled and investigated a library of 21 sulfa antibacterial drugs for their ability to restore fluconazole sensitivity in Candida albicans. Surprisingly, the majority of assayed sulfa drugs (15) were found to exhibit synergistic relationships with fluconazole by checkerboard assay with FIC values ranging from < 0.0312 to 0.25. Remarkably, five sulfa drugs, were able to revert azole resistance in a clinically achievable range. The structure-activity-relationships (SAR) of the amino benzene sulfonamide scaffold as antifungal agents were studied. We also identified the possible mechanism of the synergistic interaction of sulfa antibacterial drugs with azole antifungal drugs. Furthermore, the ability of sulfa antibacterial drugs to inhibit Candida biofilm by 40% in vitro was confirmed. In addition, effect of sulfa-fluconazole combination on Candida growth kinetics and efflux machinery was explored. Finally, using a Caenorhabditis elegans infection model, we demonstrated that the sulfa-fluconazole combination does possess potent antifungal activity in vivo reducing Candida in infected worms by ~50% compared to the control.
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