Calcineurin Inhibitors Synergize with Manogepix to Kill Diverse Human Fungal Pathogens
Abstract
:1. Introduction
2. Materials and Methods
2.1. Fungal Strains Used
2.2. Culture Media and Conditions
2.3. Dose-Response Assays
2.4. Bioinformatic Analyses
2.5. Chemical Genetic Interaction Screen
2.6. Cell Wall Staining and Quantification
2.7. Flow Cytometry
2.8. Microscopy
3. Results
3.1. Gwt1 Inhibitors Synergize with Classical Immunosuppressive Calcineurin Inhibitors
3.2. Chemical-Genetic Interactions Confirm Target-Based Synergy
3.3. Calcineurin Mediates Tolerance to Impairment of GPI-Anchor Biosynthesis at Multiple Steps in the Biosynthetic Pathway
3.4. Impairing GPI Anchor Biosynthesis at Diverse Steps Alters Cell Wall Architecture to Expose (1→3)-β-D-glucan and Increase Chitin Deposition
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
CsA | Cyclosporin A |
CFW | Calcofluor-white |
DOX | Doxycycline |
FICI | Fractional inhibitory concentration index |
GlcN-PI | glucosaminyl-phosphatidyl inositol |
GPI | glycosylphosphatidylinositol |
Gwt1 | GPI-anchored wall protein transfer |
Mcd4 | Morphogenesis checkpoint dependent 4 |
MGX | manogepix |
FMGX | fosmanogepix |
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Liston, S.D.; Whitesell, L.; Kapoor, M.; Shaw, K.J.; Cowen, L.E. Calcineurin Inhibitors Synergize with Manogepix to Kill Diverse Human Fungal Pathogens. J. Fungi 2022, 8, 1102. https://doi.org/10.3390/jof8101102
Liston SD, Whitesell L, Kapoor M, Shaw KJ, Cowen LE. Calcineurin Inhibitors Synergize with Manogepix to Kill Diverse Human Fungal Pathogens. Journal of Fungi. 2022; 8(10):1102. https://doi.org/10.3390/jof8101102
Chicago/Turabian StyleListon, Sean D., Luke Whitesell, Mili Kapoor, Karen J. Shaw, and Leah E. Cowen. 2022. "Calcineurin Inhibitors Synergize with Manogepix to Kill Diverse Human Fungal Pathogens" Journal of Fungi 8, no. 10: 1102. https://doi.org/10.3390/jof8101102