Terbinafine resistance in a pleiotropic yeast mutant is caused by a single point mutation in the ERG1 gene.
A terbinafine-resistant mutant of the yeast Saccharomyces cerevisiae with a complex pleiotropic phenotype (resistance to terbinafine and itraconazole, sensitivity to several antifungal compounds, respiration deficiency, and temperature sensitivity) has been isolated after chemical mutagenesis. Detailed analysis revealed that some of its traits (thermosensitive growth, sensitivity to the polyene antimycotic nystatin and to calcofluor white) are linked to alterations in the cell wall. A single C1288G base change in the ERG1 gene resulting in the substitution of proline by alanine at position 430 in the enzyme squalene epoxidase (Erg1p) was identified as the sole cause of terbinafine resistance. This novel mutation in the ERG1 gene confers only partial resistance of Erg1p to terbinafine, however, even the low level of resistance enables terbinafine-treated mutant cells to maintain adequate ergosterol levels over longer cultivation periods. Lack of interference of squalene accumulation with growth of terbinafine-treated mutant cells indicates that the antimycotic effect of terbinafine in S. cerevisiae may be linked primarily to ergosterol depletion.
Klobucníková
Vlasta
V
Institute of Animal Biochemistry and Genetics, Slovak Academy of Sciences, Ivanka pri Dunaji, Slovak Republic.
Kohút
Peter
P
Leber
Regina
R
Fuchsbichler
Sandra
S
Schweighofer
Natascha
N
Turnowsky
Friederike
F
Hapala
Ivan
I
D000935:Antifungal Agents / Q000494:pharmacology*; D002463:Cell Membrane Permeability; D002999:Clone Cells; D025141:Drug Resistance, Fungal / Q000235:genetics*; D004875:Ergosterol / Q000096:biosynthesis; D005800:Genes, Fungal; D009281:Naphthalenes / Q000494:pharmacology*; D010105:Oxygenases / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D050603:Squalene Monooxygenase; D000077291:Terbinafine
D000935:Antifungal Agents; D009281:Naphthalenes; D010105:Oxygenases; D050603:Squalene Monooxygenase; D000077291:Terbinafine; D004875:Ergosterol