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Enhanced Efflux Pump Expression in Candida Mutants Results in Decreased Manogepix Susceptibility
Sean D Liston1, Luke Whitesell1, Mili Kapoor2
1Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Abstract:
Manogepix is a broad-spectrum antifungal agent that inhibits glycosylphosphatidylinositol (GPI) anchor biosynthesis. Using whole-genome sequencing, we characterized two efflux-mediated mechanisms in the fungal pathogens Candida albicans and Candida parapsilosis that resulted in decreased manogepix susceptibility. In C. albicans, a gain-of-function mutation in the transcription factor gene ZCF29 activated expression of ATP-binding cassette transporter genes CDR11 and SNQ2 In C. parapsilosis, a mitochondrial deletion activated expression of the major facilitator superfamily transporter gene MDR1.
Insights
Two efflux-mediated mechanisms confer reduced susceptibility to the antifungal manogepix in Candida pathogens. These involve specific gene mutations and transporter activations in Candida albicans and Candida parapsilosis.
Area of Science:
- Mycology
- Molecular Biology
- Antimicrobial Resistance
Background:
- Manogepix is a broad-spectrum antifungal agent targeting glycosylphosphatidylinositol (GPI) anchor biosynthesis.
- Understanding resistance mechanisms is crucial for effective antifungal therapy.
Purpose of the Study:
- To characterize efflux-mediated resistance mechanisms to manogepix in fungal pathogens.
- To identify genetic alterations conferring reduced manogepix susceptibility in Candida albicans and Candida parapsilosis.
Main Methods:
- Whole-genome sequencing was employed to identify genetic changes.
- Gene expression analysis of transporter genes was performed.
Main Results:
- In Candida albicans, a ZCF29 transcription factor mutation activated CDR11 and SNQ2 transporter genes.
- In Candida parapsilosis, a mitochondrial deletion activated the MDR1 transporter gene, leading to decreased manogepix susceptibility.
Conclusions:
- Efflux pumps play a significant role in manogepix resistance in Candida species.
- Distinct genetic mechanisms drive resistance in different Candida pathogens, highlighting the need for tailored therapeutic strategies.
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