The opportunistic mold Fusarium solani is intrinsically resistant to cell wall synthesis-inhibiting echinocandins (ECs) including caspofungin and micafungin. Mutations that confer acquired EC resistance in Saccharomyces cerevisiae and other normally susceptible yeast species have been mapped to the Fks1 gene; among these is the mutation of residue 639 from Phe to Tyr (F639Y) within a region designated hotspot 1. Fks1 sequence analysis identified the equivalent of Y639 in F. solani, as well as in Scedosporium prolificans, another intrinsically EC-resistant mold. To test its role in intrinsic EC resistance, we constructed Fks1 hybrids in S. cerevisiae that incorporate F. solani hotspot 1 and flanking residues. Hybrid construction was accomplished by a PCR-based method which was validated by studies with Fks1 sequences from EC-susceptible Aspergillus fumigtus and paired EC-susceptible and resistant Candida glabrata. In support of our hypothesis, hybrid Fks1 incorporating F. solani hotspot 1 conferred significantly reduced EC susceptibility: 4 to 8-fold compared to wild-type S. cerevisiae and 8 to 32-fold compared to the same hybrid substituted with F639. We propose that Fks1 sequences represent determinants of intrinsic EC resistance in Fusarium and Scedosporium species, and potentially other fungi.
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|Evidence ID||Analyze ID||Gene||Gene Systematic Name||Phenotype||Experiment Type||Experiment Type Category||Mutant Information||Strain Background||Chemical||Details||Reference|
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