Triazole resistance mediated by mutations of a conserved active site tyrosine in fungal lanosterol 14α-demethylase
| Autor: | Brian C. Monk, Manya Sabherwal, Rajni K. Wilson, Joel D. A. Tyndall, Mikhail V. Keniya, Alia A. Sagatova |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Posaconazole Antifungal Agents Saccharomyces cerevisiae Proteins Protein Conformation Itraconazole 030106 microbiology Mutant Mutation Missense Triazole Microbial Sensitivity Tests Saccharomyces cerevisiae Crystallography X-Ray Article 03 medical and health sciences chemistry.chemical_compound Cytochrome P-450 Enzyme System Drug Resistance Fungal Catalytic Domain medicine Voriconazole Multidisciplinary biology Lanosterol Active site Triazoles 030104 developmental biology Amino Acid Substitution Biochemistry chemistry biology.protein Tyrosine Mutant Proteins Fluconazole medicine.drug |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep26213 |
| Popis: | Emergence of fungal strains showing resistance to triazole drugs can make treatment of fungal disease problematic. Triazole resistance can arise due to single mutations in the drug target lanosterol 14α-demethylase (Erg11p/CYP51). We have determined how commonly occurring single site mutations in pathogenic fungi affect triazole binding using Saccharomyces cerevisiae Erg11p (ScErg11p) as a target surrogate. The mutations Y140F/H were introduced into full-length hexahistidine-tagged ScErg11p. Phenotypes and high-resolution X-ray crystal structures were determined for the mutant enzymes complexed with short-tailed (fluconazole and voriconazole) or long-tailed (itraconazole and posaconazole) triazoles and wild type enzyme complexed with voriconazole. The mutations disrupted a water-mediated hydrogen bond network involved in binding of short-tailed triazoles, which contain a tertiary hydroxyl not present in long-tailed triazoles. This appears to be the mechanism by which resistance to these short chain azoles occurs. Understanding how these mutations affect drug affinity will aid the design of azoles that overcome resistance. |
| Databáze: | OpenAIRE |
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