Terbinafine Resistance Mediated by Salicylate 1-Monooxygenase in Aspergillus nidulans
| Autor: | Rolf A. Prade, E. M. F. Rocha, Nilce Maria Martinez-Rossi, Marcia A. S. Graminha |
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| Rok vydání: | 2004 |
| Předmět: |
Antifungal Agents
Transcription Genetic medicine.drug_class Genes Fungal Antibiotics Mutant DNA Fragmentation Naphthalenes medicine.disease_cause Aspergillus nidulans Mixed Function Oxygenases Microbiology Transformation Genetic Drug Resistance Fungal Mechanisms of Resistance medicine Pharmacology (medical) DNA Fungal Terbinafine Gene DNA Primers Gene Library Pharmacology biology Reverse Transcriptase Polymerase Chain Reaction Wild type Chromosome Mapping Blotting Northern biology.organism_classification Culture Media Blotting Southern Transformation (genetics) Infectious Diseases Dermatophyte Fatty Acid Synthases medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 48:3530-3535 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | Resistance to antifungal agents is a recurring and growing problem among patients with systemic fungal infections. UV-induced Aspergillus nidulans mutants resistant to terbinafine have been identified, and we report here the characterization of one such gene. A sib-selected, 6.6-kb genomic DNA fragment encodes a salicylate 1-monooxygenase (salA), and a fatty acid synthase subunit (fasC) confers terbinafine resistance upon transformation of a sensitive strain. Subfragments carrying salA but not fasC confer terbinafine resistance. salA is present as a single-copy gene on chromosome VI and encodes a protein of 473 amino acids that is homologous to salicylate 1-monooxygenase, a well-characterized naphthalene-degrading enzyme in bacteria. salA transcript accumulation analysis showed terbinafine-dependent induction in the wild type and the UV-induced mutant Terb7, as well as overexpression in a strain containing the salA subgenomic DNA fragment, probably due to the multicopy effect caused by the transformation event. Additional naphthalene degradation enzyme-coding genes are present in fungal genomes, suggesting that resistance could follow degradation of the naphthalene ring contained in terbinafine. The incidence of fungal infections has increased in the last 20 years, primarily because of the increase in the number of immunocompromised patients due to AIDS, malnutrition, the indiscriminate use of antibiotics, chemotherapy, and artificial immunosuppressive treatment in organ transplants (17). In addition, the widespread use of antifungal agents has led to clinical resistance. Thus, insights into molecular and genetic mechanisms involved in resistance are needed to define treatment strategies and to design new antifungal drugs. Terbinafine is a generic antifungal agent used to treat superficial mycoses such as dermatophyte onychomycosis, dermato |
| Databáze: | OpenAIRE |
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