title: Sphingolipids mediate differential echinocandin susceptibility in Candida albicans and Aspergillus nidulans.
abstract: The cell wall synthesis-inhibiting echinocandins, including caspofungin and micafungin, play important roles in the treatment of candidiasis and aspergillosis. Previous studies revealed that, in the haploid yeast Candida glabrata, sphingolipid biosynthesis pathway mutations confer caspofungin reduced susceptibility (CRS) but micafungin increased susceptibility (MIS). Here, we describe one Candida albicans strain (of 10 tested) that similarly yields CRS-MIS mutants at relatively high frequency. Mutants demonstrated increased levels of long-chain bases (sphingolipid pathway intermediates) and, unique to this strain, loss of His104/Pro104 heterozygosity in the TSC13-encoded enoyl reductase. CRS-MIS was similarly observed in a C. albicans homozygous fen1Δ fen12Δ laboratory strain and in diverse wild-type strains following exogenous long-chain-base treatment. Analogous to these results, CRS-MIS was demonstrated in an Aspergillus nidulans basA mutant encoding defective sphingolipid C4-hydroxylase and in its wild-type parent exposed to long-chain bases. Sphingolipids likely modulate echinocandin interaction with their Fks membrane target in all susceptible fungi, with potential implications for optimizing therapy with existing antifungals and the development of novel agents.
authors.affiliation: Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Kelley R
authors.initials: KR
authors.lastname: Healey
authors.affiliation: Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Challa
authors.affiliation: MicrobiType LLC, Plymouth Meeting, Pennsylvania, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Edlind
authors.affiliation: Drexel University College of Medicine, Philadelphia, Pennsylvania, USA santosh.katiyar@drexelmed.edu.
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Katiyar
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001233:Aspergillus nidulans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D054714:Echinocandins / Q000494:pharmacology*; D005260:Female; D005816:Genetic Complementation Test; D051379:Mice; D058885:Multilocus Sequence Typing; D013107:Sphingolipids / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D013107:Sphingolipids
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