Metabolic control of antifungal drug resistance.
Fungi have evolved an elegant repertoire of mechanisms to survive the cellular stress exerted by antifungal drugs such as azoles, which inhibit ergosterol biosynthesis inducing cell membrane stress. The evolution and maintenance of diverse resistance phenotypes is contingent upon cellular circuitry regulated by the molecular chaperone Hsp90 and its client protein calcineurin. Here, we establish a novel role for nutrients and nutrient signaling in azole resistance. The vulnerability of Saccharomyces cerevisiae azole resistance phenotypes to perturbation was contingent upon specific auxotrophies. Using strains that acquired azole resistance by Erg3 loss of function as a model for resistance that depends on cellular stress responses, we delineated genetic and environmental factors that mitigate the translation of genotype into resistance phenotype. Compromising a global regulator that couples growth and metabolism to environmental cues, Tor kinase, provides a powerful strategy to abrogate drug resistance of S. cerevisiae and Candida albicans with broad therapeutic potential.
Robbins
Nicole
N
Department of Molecular Genetics, University of Toronto, Toronto, Ont., Canada M5S 1A8.
Collins
Cathy
C
Morhayim
Jess
J
Cowen
Leah E
LE
D000596:Amino Acids / Q000378:metabolism; D000935:Antifungal Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D003470:Culture Media / Q000737:chemistry; D025141:Drug Resistance, Fungal / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D016681:Genome, Fungal / Q000235:genetics; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology
D000596:Amino Acids; D000935:Antifungal Agents; D001393:Azoles; D050976:Basic-Leucine Zipper Transcription Factors; D003470:Culture Media; C501391:GCN4 protein, S cerevisiae; C074510:HSP82 protein, S cerevisiae; D018841:HSP90 Heat-Shock Proteins; D029701:Saccharomyces cerevisiae Proteins; D010088:Oxidoreductases; C039306:sterol delta-5 desaturase; D019703:Calcineurin; D020123:Sirolimus