RRC ID 60587
Author Abastabar M, Hosseini T, Valadan R, Lagzian M, Haghani I, Aslani N, Badali H, Nouripour-Sisakht S, Nazeri M, Gholami S, Vakili M, Bowyer P, Shokohi T, Hedayati MT.
Title Novel Point Mutations in cyp51A and cyp51B Genes Associated with Itraconazole and Posaconazole Resistance in Aspergillus clavatus Isolates.
Journal Microb Drug Resist
Abstract Aspergillus clavatus is a common environmental species known to cause occupational allergic disease in grain handlers. We have recently observed azole-resistant isolates of this fungus as a cause of onychomycosis. To further characterize the cause of resistance, the genes encoding 14 α-sterol demethylase enzyme (cyp51A and cyp51B) were characterized and analyzed in 9 ITC-susceptible isolates and 6 isolates with high minimum inhibitory concentrations (MICs) of clinical (nail and sputum) and environmental A. clavatus strains. We found that six isolates with itraconazole MIC >16 mg/L demonstrated nonsynonymous mutations, including V51I, L378P, E483K, and E506G, and synonymous mutations, including F53F, A186A, Q276Q, and H359H. Moreover, P486S was detected in five strains with ITR MIC >16 mg/L. One mutation, F324S, was detected in an isolate with posaconazole MIC >16 mg/L. The effect of E483K and P486S mutations of CYP51A on azole resistance was further investigated using homology modeling and molecular dynamics. We found that E483K and P486S mutations were located near the ligand access channel of CYP51A that could partly lead to narrowing the entry of the ligand access channels. Therefore, we concluded that E483K and P486S mutations may potentially contribute to the limited access of inhibitors to the binding pocket and therefore confer resistance to azole agents.
Volume 25(5)
Pages 652-662
Published 2019-6
DOI 10.1089/mdr.2018.0300
PMID 30657433
MeSH Amino Acid Sequence Antifungal Agents / chemistry* Antifungal Agents / pharmacology Aspergillosis / drug therapy Aspergillosis / microbiology Aspergillus / drug effects Aspergillus / enzymology Aspergillus / genetics* Aspergillus / isolation & purification Base Sequence Binding Sites Cytochrome P-450 Enzyme System / chemistry* Cytochrome P-450 Enzyme System / genetics Cytochrome P-450 Enzyme System / isolation & purification Cytochrome P-450 Enzyme System / metabolism Drug Resistance, Fungal / genetics Fungal Proteins / chemistry* Fungal Proteins / genetics Fungal Proteins / isolation & purification Fungal Proteins / metabolism Gene Expression Humans Itraconazole / chemistry* Itraconazole / pharmacology Microbial Sensitivity Tests Molecular Docking Simulation Molecular Dynamics Simulation Nails / microbiology Point Mutation* Protein Binding Protein Conformation, alpha-Helical Protein Conformation, beta-Strand Protein Interaction Domains and Motifs Sequence Alignment Sputum / microbiology Structural Homology, Protein Triazoles / chemistry* Triazoles / pharmacology
IF 2.397
Times Cited 3
Resource
General Microbes JCM10080