Lectin-Fc(IgG) fusion proteins exhibit antifungal activity against the emerging multidrug-resistant pathogen <i>Candida auris</i>

<i>Candida auris</i> is an emerging fungal pathogen recognized among the Centers for Disease Control and Prevention's urgent threats and designated a critical priority by the World Health Organization due to its global spread, high mortality rates, potential for pan-drug resistance, and its persistent transmission within healthcare settings. The clinical management of <i>C. auris</i> infections is further hindered by the lack of both rapid/specific diagnosis and effective antifungals. These challenges emphasize the urgent need for alternative therapeutic strategies. In this study, we investigated the antifungal, immunomodulatory, and protective effects of engineered Lectin-Fc(IgG) fusion proteins against a fluconazole-resistant <i>C. auris</i> strain. Specifically, Dectin-1-Fc(IgG2a), Dectin-1-Fc(IgG2b), and wheat germ agglutinin (WGA)-Fc(IgG2a) demonstrated dose-dependent binding to key fungal cell wall components, β-1,3-glucan and chitin, with Dectin-1-Fc(IgG2b) exhibiting the highest reactivity, followed by Dectin-1-Fc(IgG2a) and WGA-Fc(IgG2a). <i>In vitro</i>, all constructs exhibited fungistatic activity and reduced the biofilm biomass and metabolism, with the Dectin-1-Fc(IgG) variants displaying the most potent effects. As opsonins, Lectin-Fc(IgG)s significantly enhanced the macrophage-yeast association and macrophage-mediated killing of <i>C. auris</i>. In a systemic murine <i>C. auris</i> infection model, a single therapeutic administration of Dectin-1-Fc(IgG2b) or WGA-Fc(IgG2a) conferred 100% protection, while Dectin-1-Fc(IgG2a) achieved >80% protection, with all treated mice manifesting clinical improvement. Quantification of fungal burden at day 7 post-infection revealed at least a ~1 log reduction in colony-forming units in the spleen, kidney, and liver of Lectin-Fc(IgG)-treated animals. Cytokine profiling indicated a Th1-type-skewed immune response in Lectin-Fc(IgG)-treated mice. Collectively, these findings support the antifungal and immunotherapeutic potential of Lectin-Fc(IgG)s against <i>C. auris</i>, offering a novel broad-spectrum strategy to overcome current therapeutic limitations.