Identification of 14 alpha-lanosterol demethylase (CYP51) in Scedosporium species [PublishAheadOfPrint]

Scedosporium spp. cause infections (scedosporiosis) in both immunocompetent and immunocompromised individuals and may persistently colonise the respiratory tract in patients with cystic fibrosis (CF). They are less susceptible against azoles when compared with other moulds such as Aspergillus, suggesting the presence of resistance mechanisms. It can be hypothesised that the decreased susceptibility of Scedosporium spp. to azoles is also CYP51 dependant. Analysis of the S. apiospermum and S. aurantiacum genome revealed one CYP51 gene encoding the 14 alpha-lanosterol demethylase. This gene of 159 clinical or environmental Scedosporium and three Lomentospora prolificans isolates has been sequenced and analysed. The Scedosporium CYP51 protein clustered with the group of known CYP51B orthologues and showed species-specific polymorphisms. A tandem repeat in the 5' upstream region of Scedosporium CYP51 like that in A. fumigatus could not be detected. Species-specific amino acid (aa) alterations in CYP51 of S. boydii, S. ellipsoideum, S. dehoogii and S. minutisporum isolates were located on positions that have not been described as having an impact on azole susceptibility. In contrast, two of the three S. apiospermum-specific aa changes (Y136F and G464S) corresponded to respective mutations in A. fumigatus CYP51A at aa position 121 and 448 (Y121F and G448S) that had been linked to azole resistance.

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