A Cationic Supramolecule With Potent Antifungal Activity, Single‐Species Selectivity, and Strong Synergy With Echinocandins

ABSTRACT Claiming 3.8 million lives annually, fungal pathogens represent a major health threat, where Candida species are the leading cause with >40% mortality rates. Despite rising prevalence of life‐threatening fungal species/strains, progress in developing new antifungal agents remains limited. Here, we report a new synthetic membrane‐active cationic supramolecule Gua‐SMACS‐16 that exhibits high antifungal potency and selectivity for Candida tropicalis (MIC = 0.4‐0.8 µM) without affecting other phylogenetically close species in the Candida genus, non‐ Candida fungal, or common opportunistic bacterial species in the human microbiome. Gua‐SMACS‐16 exerts its activity by disrupting the cytoplasmic membrane, while its C. tropicalis selectivity is attributed to the species’ low cell wall β‐glucan level, which fails to block the supramolecule entry. It also exhibits minimal toxicity to mammalian cells and zebrafish embryos, suggesting a high clinical translation potential. Moreover, an ultra‐strong synergy was observed between Gua‐SMACS‐16 and caspofungin, a clinical antifungal drug inhibiting 1,3‐β‐glucan synthase, reducing their MICs by orders of magnitude against all tested Candida species including the intractable C. auris . Together, this work highlights the importance of cell wall glucan for membrane‐active antifungal amphiphiles, provides a novel design principle for species‐specific antifungal agents, and uncovers a new approach to developing synergizers for combination antifungal therapy.