Distinct binding modes shape exploitable asymmetries between echinocandin and triterpenoid resistance landscapes in Fks1

Ibrexafungerp selects a distinct, ibrexafungerp-specific resistance cluster downstream of Fks1 hotspot 2, defining a novel triterpenoid-specific hotspot 4 in Saccharomyces cerevisiae.

• Why it matters: It is unclear how echinocandin versus triterpenoid binding differences reshape which Fks1 mutations confer resistance, limiting prediction of resistance evolution and treatment choices.
• What they did: Using deep mutational scanning across 159 Fks1 residues spanning three canonical hotspots and flanking regions in Saccharomyces cerevisiae, they measured variant effects under drug selection and then confirmed patterns in Candida auris and S. cerevisiae susceptibility tests.
• The result: They found widespread position-specific cross-resistance and differential resistance, redefined echinocandin hotspot boundaries, and used structure-guided ligand placement plus molecular dynamics and DMS-informed pose selection to link phenotypes to distinct interaction networks.

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