Role of Aspergillus lentulus14-α Sterol Demethylase (Cyp51A) in Azole Drug Susceptibility

ABSTRACTRecent studies have demonstrated that some morphologically atypical Aspergillus fumigatusstrains 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. lentuluscytochrome P450 14-α sterol demethylases, encoded by A. lentuluscyp51A (Alcyp51A) and Alcyp51Bgenes, were identified. Targeted cyp51Agene knockout in A. lentulusshowed that the intrinsic azole resistance of this species is cyp51Adependent. The Δcyp51Astrain was morphologically indistinguishable from the A. lentuluswild-type strain, retaining the ability to cause pulmonary disease in neutropenic mice. The heterologous expression of A. lentuluscyp51Awas performed in an A. fumigatuscyp51A-deficient strain, confirming that Cyp51A is responsible for the differences in A. lentulus-azole drug interaction.