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CYP51 Paralogue Structure Is Associated with Intrinsic Azole Resistance in Fungi
N Van Rhijn1, M Bromley1, M Richardson1,2
1Manchester Fungal Infection Group, Division of Infection, Immunity and Respiratory Medicine, The University of Manchestergrid.5379.8, Manchester, United Kingdom.
Mbio
|October 5, 2021
Summary
Azole antifungals are key treatments for fungal infections. This study found that intrinsically resistant fungi possess extra copies of the CYP51 gene, which can confer drug resistance when transferred to sensitive fungi.
Area of Science:
- Medical Mycology
- Fungal Genomics
- Antifungal Drug Resistance
Background:
- Azole antifungals are crucial for treating human fungal diseases.
- Intrinsic azole resistance in fungi is common but poorly understood.
- The target of azoles is lanosterol demethylase (CYP51).
Purpose of the Study:
- To investigate the mechanisms of intrinsic azole resistance in fungal species.
- To identify novel genetic factors contributing to azole resistance.
- To compare CYP51 gene structures in azole-resistant and azole-sensitive fungi.
Main Methods:
- Genome sequencing of five azole-resistant Penicillium isolates.
- Comparative analysis of CYP51 paralogues across 46 fungal isolates.
- Functional analysis involving gene transfer to assess resistance conferral.
Main Results:
- A novel CYP51 paralogue, CYP51D, was identified in azole-resistant isolates and associated with resistance.
- A CYP51A paralogue, CYP51A2, was found in resistant isolates and conferred resistance upon transfer.
- Extra copies of CYP51 genes were linked to intrinsic azole resistance.
Conclusions:
- Novel CYP51 paralogues (CYP51D and CYP51A2) represent a significant mechanism of azole resistance.
- The presence of alternative CYP51 gene copies can explain intrinsic antifungal resistance.
- Genome sequencing can predict azole resistance in clinically important fungal species.
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