ABSTRACT
Replacement of phenylalanine with leucine at position 391 in squalene epoxidase was identified as being responsible for terbinafine resistance in mutants of Aspergillus nidulans. The equivalent mutation was engineered into the ergA gene of Aspergillus fumigatus, resulting in an F389L substitution that also conferred resistance to this pathogenic mold.
Subject(s)
Amino Acid Substitution , Antifungal Agents/pharmacology , Aspergillus fumigatus/drug effects , Drug Resistance, Fungal/genetics , Naphthalenes/pharmacology , Squalene Monooxygenase/genetics , Amino Acid Sequence , Aspergillus fumigatus/enzymology , Aspergillus fumigatus/genetics , Fungal Proteins/chemistry , Fungal Proteins/genetics , Microbial Sensitivity Tests , Molecular Sequence Data , Squalene Monooxygenase/chemistry , TerbinafineABSTRACT
AIMS: To determine the pattern and the genetic basis of resistance to terbinafine, a drug extensively used for the treatment of fungal infections in humans. METHODS AND RESULTS: Four resistant mutants from Aspergillus nidulans isolated after irradiation with ultraviolet light were crossed with the master strain F (MSF). Genetic analysis revealed that a single gene, located on chromosome IV, is responsible for resistance to terbinafine and that the alleles responsible for this resistance in these mutants are of a codominant or dominant nature at high terbinafine concentrations. Furthermore, the interaction of this mutation with another one identified on chromosome II causes the double mutant to be highly resistant. CONCLUSIONS: Periodic surveillance of antimycotic susceptibility would be an important measure in detecting the emergence and spread of resistance. Mutation in a single gene could be responsible for resistance to terbinafine and a genic interaction may be responsible for a higher level of antimycotic resistance. SIGNIFICANCE AND IMPACT OF THE STUDY: The understanding of the mechanisms that lead to changes in the sensitivity of a fungus to a given antifungal agent is important both in order to define strategies for the use of such agent and to guide the development of new antifungal agents.
