Alkaloids solenopsins from fire ants display <i>in vitro</i> and <i>in vivo</i> activity against the yeast <i>Candida auris</i>

The urgency surrounding <i>Candida auris</i> as a public health threat is highlighted by both the Center for Disease Control (CDC) and World Health Organization (WHO) that categorized this species as a priority fungal pathogen. Given the current limitations of antifungal therapy for <i>C. auris</i>, particularly due to its multiple resistance to the current antifungals, the identification of new drugs is of paramount importance. Some alkaloids abundant in the venom of the red invasive fire ant (<i>Solenopsis invicta</i>), known as solenopsins, have garnered attention as potent inhibitors of bacterial biofilms, and there are no studies demonstrating such effects against fungal pathogens. Thus, we herein investigated the antibiotic efficacy of solenopsin alkaloids against <i>C. auris</i> biofilms and planktonic cells. Both natural and synthetic solenopsins inhibited the growth of <i>C. auris</i> strains from different clades, including fluconazole and amphotericin B-resistant isolates. Such alkaloids also inhibited matrix deposition and altered cellular metabolic activity of <i>C. auris</i> in biofilm conditions. Mechanistically, the alkaloids compromised membrane integrity as measured by propidium iodide uptake in exposed planktonic cells. Additionally, combining the alkaloids with AMB yielded an additive antifungal effect, even against AMB-resistant strains. Finally, both extracted solenopsins and the synthetic analogues demonstrated protective effect <i>in vivo</i> against <i>C. auris</i> infection in the invertebrate model <i>Galleria mellonella</i>. These findings underscore the potent antifungal activities of solenopsins against <i>C. auris</i> and suggest their inclusion in future drug development. Furthermore, exploring derivatives of solenopsins could reveal novel compounds with therapeutic promise.