Unveiling the Molecular Architecture of Candida auris Ribosome

Candida auris is an emerging multidrug-resistant fungal pathogen causing life- threatening invasive candidiasis and bloodstream infections, posing major global health challenges. Protein translation in pathogenic fungi remains poorly characterized. Using cryo-electron microscopy and single-particle reconstruction, we determined high-resolution structures of the 80S ribosome from C. auris in its vacant state and bound to three inhibitors: cycloheximide (CHX), blasticidin-S (BLS), and geneticin (G418). We discovered a unique substitution of a key nucleotide in the P-site of the small ribosomal subunit (C1160), which may alter ribosome-tRNA interactions and translation fidelity. Comparative analysis of inhibitor binding showed CHX resistance in only two examined Candida species. BLS binding differed little between C. auris and Saccharomyces cerevisiae, yet C. auris was more sensitive. G418 displayed promiscuous binding at multiple nonspecific sites, while its main site at the decoding center remained highly conserved among Candida species. These results reveal the previously uncharacterized structure of the C. auris ribosome and its distinctive features, offering opportunities to design targeted antifungal therapies against multidrug resistance and suggesting structural biomarkers for predicting antifungal susceptibility in clinical settings. Together, these structural and functional insights deepen our understanding of C. auris biology and help prioritize ribosomal sites for future antifungal drug development.