Inhibiting Mrt4-rRNA interaction with fumaramidmycin-based derivatives as an unexploited antifungal strategy

ABSTRACT: The rise of drug resistance and limitations of current antifungal treatments highlight the urgent need for innovative antifungal strategies. Here we present the development of cis-fumaramidmycin-derived analogues as a novel chemotype inhibiting the interactions of ribosome assembly factor Mrt4 with rRNA to combat fungal infections. Through antifungal screening, we identified a promising lead 20 with strong efficacy against various drug-resistant fungi, including notorious super-fungus Candida auris. A comprehensive approach combining active-and-inactive-based protein profiling (AIBPP), chemical-genetic profiling, and fluorescence polarization revealed that the antifungal activity of 20 is primarily due to selectively inhibiting essential CaMrt4-rRNA interaction by conjointly covalent engaging Cys96&Cys189 on CaMrt4 but inactive for HuMrt4-rRNA interaction, thereby disrupting fungal ribosomal assembly. Therapeutic efficacy of 20 in both Galleria mellonella larvae and murine candidiasis models validate this antifungal strategy. Collectively, our studies provide a new and much-need therapeutic strategy to address the rapidly rising burden of drug-resistant fungal infections.

INSTRUMENT(S):

ORGANISM(S): Candida Albicans (yeast)

TISSUE(S): Cell Culture, Fungal Cell

DISEASE(S): Fungal Infectious Disease

SUBMITTER: Hu Xiuqi  

LAB HEAD: Hu Xiuqi

PROVIDER: PXD068797 | Pride | 2026-04-27

REPOSITORIES: pride