Prochelators modulate azole activity against Candida albicans in a metal-dependent manner.

Candida albicans is an opportunstic fungal pathogen of growing clinical concern, in part due to antifungal drug tolerance. Here we report a thiol-activated prochelation strategy that modulates the activity of azole antifungals against C. albicans in a manner influenced by the degree of azole stress as well as the metal composition of the growth medium. We identify two disulfide-linked prochelators containing aroylhydrazone (AH1-S)2 or thiosemicarbazone (IT1-S)2 structures that impact C. albicans growth in both a standard laboratory strain and a fluconazole-resistant clinical isolate. A combination of metal analysis and EPR spectroscopy of treated cells shows that (AH1-S)2 redistributes intracellular iron stores by forming an intracellular iron chelator complex. We also show that (AH1-S)2 promotes copper accumulation under otherwise non-toxic copper conditions, resulting in fungicidal activity.