Identification of 14-α-Lanosterol Demethylase (CYP51) in Scedosporium Species

Area of Science:

• Medical Mycology
• Molecular Biology
• Antifungal Resistance

Background:

• Scedosporium species cause scedosporiosis in immunocompetent and immunocompromised individuals.
• These fungi, often found in cystic fibrosis patients, show reduced susceptibility to azole antifungals compared to Aspergillus species.
• This suggests underlying azole resistance mechanisms, potentially involving the CYP51 gene.

Purpose of the Study:

• To investigate the role of the CYP51 gene in azole susceptibility in Scedosporium species.
• To identify potential genetic mechanisms contributing to azole resistance in Scedosporium and Lomentospora prolificans.

Main Methods:

• Genome analysis of Scedosporium apiospermum and Scedosporium aurantiacum to identify CYP51 genes.
• Sequencing and analysis of the CYP51 gene from 159 clinical/environmental Scedosporium isolates and 3 Lomentospora prolificans isolates.
• Comparative analysis of Scedosporium CYP51 protein sequences with known orthologues and identification of species-specific alterations.

Main Results:

• A single CYP51 gene encoding 14-α-lanosterol demethylase was identified in Scedosporium apiospermum and Scedosporium aurantiacum.
• Scedosporium CYP51 proteins clustered with CYP51B orthologues and exhibited species-specific polymorphisms.
• Two specific amino acid changes (Y136F and G464S) in Scedosporium CYP51, analogous to mutations in Aspergillus fumigatus CYP51A, were linked to azole resistance.

Conclusions:

• The CYP51 gene is a potential target for understanding azole resistance in Scedosporium species.
• Specific amino acid alterations in Scedosporium CYP51, particularly those mirroring known resistance mutations in Aspergillus, are implicated in reduced azole susceptibility.
• Further research into these CYP51 variations could inform strategies for treating scedosporiosis.