title: Role of Aspergillus lentulus 14-α sterol demethylase (Cyp51A) in azole drug susceptibility.
abstract: Recent studies have demonstrated that some morphologically atypical Aspergillus fumigatus strains are different species belonging to the section Fumigati. Aspergillus lentulus, one of these sibling species, is increasingly reported in patients under corticosteroid treatment. MICs of most antifungals in clinical use are elevated against A. lentulus, and it shows primary resistance to azole drugs. Two A. lentulus cytochrome P450 14-α sterol demethylases, encoded by A. lentulus cyp51A (Alcyp51A) and Alcyp51B genes, were identified. Targeted cyp51A gene knockout in A. lentulus showed that the intrinsic azole resistance of this species is cyp51A dependent. The Δcyp51A strain was morphologically indistinguishable from the A. lentulus wild-type strain, retaining the ability to cause pulmonary disease in neutropenic mice. The heterologous expression of A. lentulus cyp51A was performed in an A. fumigatus cyp51A-deficient strain, confirming that Cyp51A is responsible for the differences in A. lentulus-azole drug interaction.
authors.affiliation: Servicio de Micologia, Centro Nacional de Microbiologia. Instituto de Salud Carlos III, Carretera Majadahonda-Pozuelo Km2, 28220 Madrid, Spain. emellado@isciii.es
authors.forename: Emilia
authors.initials: E
authors.lastname: Mellado
authors.forename: Laura
authors.initials: L
authors.lastname: Alcazar-Fuoli
authors.forename: Manuel
authors.initials: M
authors.lastname: Cuenca-Estrella
authors.forename: Juan L
authors.initials: JL
authors.lastname: Rodriguez-Tudela
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001230:Aspergillus / Q000187:drug effects* / Q000201:enzymology* / Q000472:pathogenicity; D001393:Azoles / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D025141:Drug Resistance, Fungal / Q000235:genetics*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D055732:Pulmonary Aspergillosis / Q000382:microbiology / Q000473:pathology; D058886:Sterol 14-Demethylase / Q000235:genetics / Q000378:metabolism; D014774:Virulence
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D005656:Fungal Proteins; D003577:Cytochrome P-450 Enzyme System; C465526:cytochrome P-450 CYP51A, Aspergillus; D058886:Sterol 14-Demethylase