Calcineurin Inhibitors Synergize with Manogepix to Kill Diverse Human Fungal Pathogens

Invasive fungal infections have mortality rates of 30–90%, depending on patient co-morbidities and the causative pathogen. The frequent emergence of drug resistance reduces the efficacy of currently approved treatment options, highlighting an urgent need for antifungals with new modes of action. Add...

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Bibliographic Details
Published in:Journal of fungi (Basel) 2022-10, Vol.8 (10), p.1102
Main Authors: Liston, Sean D., Whitesell, Luke, Kapoor, Mili, Shaw, Karen J., Cowen, Leah E.
Format: Article
Language:English
Subjects:
Acyltransferase
Antifungal agents
APX001
APX001A
Biosynthesis
Calcineurin
Calcineurin inhibitors
Cell walls
Drug resistance
Drugs
Endoplasmic reticulum
Enzymes
FMGX
fosmanogepix
Fungal infections
Fungi
Glucans
Glycosylphosphatidylinositol
Immunostimulation
Immunosuppressive agents
manogepix
MGX
Pathogens
Pharmaceuticals
Protein phosphatase
Proteins
Signal transduction
Subcultures
Synergism
Tacrolimus
Yeast
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Summary:Invasive fungal infections have mortality rates of 30–90%, depending on patient co-morbidities and the causative pathogen. The frequent emergence of drug resistance reduces the efficacy of currently approved treatment options, highlighting an urgent need for antifungals with new modes of action. Addressing this need, fosmanogepix (N-phosphonooxymethylene prodrug of manogepix; MGX) is the first in a new class of gepix drugs, and acts as a broad-spectrum, orally bioavailable inhibitor of the essential fungal glycosylphosphatidylinositol (GPI) acyltransferase Gwt1. MGX inhibits the growth of diverse fungal pathogens and causes accumulation of immature GPI-anchored proteins in the fungal endoplasmic reticulum. Relevant to the ongoing clinical development of fosmanogepix, we report a synergistic, fungicidal interaction between MGX and inhibitors of the protein phosphatase calcineurin against important human fungal pathogens. To investigate this synergy further, we evaluated a library of 124 conditional expression mutants covering 95% of the genes encoding proteins involved in GPI-anchor biosynthesis or proteins predicted to be GPI-anchored. Strong negative chemical-genetic interactions between the calcineurin inhibitor FK506 and eleven GPI-anchor biosynthesis genes were identified, indicating that calcineurin signalling is required for fungal tolerance to not only MGX, but to inhibition of the GPI-anchor biosynthesis pathway more broadly. Depletion of these GPI-anchor biosynthesis genes, like MGX treatment, also exposed fungal cell wall (1→3)-β-D-glucans. Taken together, these findings suggest the increased risk of invasive fungal infections associated with use of calcineurin inhibitors as immunosuppressants may be mitigated by their synergistic fungicidal interaction with (fos)manogepix and its ability to enhance exposure of immunostimulatory glucans.
ISSN:2309-608X
2309-608X
DOI:10.3390/jof8101102