title: Fitness and virulence costs of Candida albicans FKS1 hot spot mutations associated with echinocandin resistance.
abstract: The identification of FKS1 mutations in Candida albicans associated with echinocandin resistance has raised concerns over the spread of drug-resistant strains. We studied the impact of fks1 mutations on C. albicans virulence and fitness. Compared with wild-type strains for FKS1, echinocandin-resistant C. albicans strains with homozygous fks1 hot-spot mutations had reduced maximum catalytic capacity of their glucan synthase complexes and thicker cell walls attributable to increased cell wall chitin content. The fks1 mutants with the highest chitin contents had reduced growth rates and impaired filamentation capacities. Fks1 mutants were hypovirulent in fly and mouse models of candidiasis, and this phenotype correlated with the cell wall chitin content. In addition, we observed reduced fitness of echinocandin-resistant C. albicans in competitive mixed infection models. We conclude that fks1 mutations that confer echinocandin resistance come at fitness and virulence costs, which may limit their epidemiological and clinical impact.
authors.affiliation: Department of Infectious Diseases, Infection Control and Employee Health, the University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Ronen
authors.initials: R
authors.lastname: Ben-Ami
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Effron
authors.forename: Russell E
authors.initials: RE
authors.lastname: Lewis
authors.forename: Soledad
authors.initials: S
authors.lastname: Gamarra
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Leventakos
authors.forename: David S
authors.initials: DS
authors.lastname: Perlin
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity*; D002177:Candidiasis / Q000382:microbiology; D025141:Drug Resistance, Fungal / Q000235:genetics* / Q000502:physiology; D054714:Echinocandins / Q000494:pharmacology*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal / Q000502:physiology; D056084:Genetic Fitness; D008264:Macrophages / Q000502:physiology; D051379:Mice; D009154:Mutation; D014774:Virulence
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D005656:Fungal Proteins