A zinc-chelating cyclic alkyl polyamine compound is efficient and safe in a murine model of multidrug-resistant <i>Candida auris</i> infection

<i>Candida auris</i> is an emerging multidrug-resistant fungal pathogen associated with severe nosocomial outbreaks and high mortality rates worldwide. The increasing incidence of antifungal resistance underscores the urgent need for agents with novel mechanisms of action. APC6 is a zinc-chelating cyclic alkyl polyamine compound that selectively disrupts zinc homeostasis in fungal cells. We have previously reported that APC6 has antifungal activity against <i>Candida</i> spp., including <i>Candida auris</i>, and low cytotoxicity to human cells. In this study, we evaluated the <i>in vivo</i> efficacy and safety of APC6 using a neutropenic murine model of disseminated <i>C. auris</i> infection. APC6 significantly improved survival and reduced fungal burden in the liver, kidneys, and brain. At a therapeutic dose of 15 mg/kg, APC6 had similar or superior antifungal activity to that of amphotericin B. Histopathological analysis revealed a decreased number of fungal microabscesses in APC6-treated tissues. No significant adverse effects were observed following 28-day repeated intraperitoneal administration, and the Ames assay revealed no mutagenic activity. To our knowledge, this is the first study to demonstrate that a zinc-chelating compound can improve survival and reduce organ fungal burden in a mammalian model of drug-resistant <i>C. auris</i> infection. These results highlight APC6 as a promising lead compound targeting fungal zinc homeostasis and support its further development as a novel antifungal agent.