Caspofungin binding to iron compromises its antifungal efficacy against Candida albicans.

Echinocandins, which inhibit the synthesis of β-1,3-D-glucans, essential components of the fungal cell wall, are frontline drugs for invasive fungal infections (IFIs) caused by Candida spp. Recent in vitro studies have suggested that iron overload may reduce the efficacy of the echinocandin caspofungin against Candida albicans by altering its cell wall composition. Here, we show that iron loading conditions which do not interfere with the cell wall composition are still capable of recapitulating the caspofungin-resistant phenotype induced by iron. Spectroscopic analyses provided evidence that caspofungin binds to iron through its ethylenediamine moiety and two amide groups. Consistent with the in vitro activity of β-1,3-D-glucan synthase, the target of caspofungin, molecular dynamics simulations revealed that iron binding induces conformational changes in caspofungin, which may reduce its ability to inhibit the enzyme. Importantly, the in vivo antifungal efficacy of caspofungin was compromised in a Galleria mellonella model of IFI caused by C. albicans simulating a context of iron overload. This effect may extend beyond C. albicans infections, as the antagonism between iron and caspofungin was also observed in other medically important fungi causing IFIs.