Macrophage internalization creates a multidrug-tolerant fungal persister reservoir and facilitates the emergence of drug resistance

Amir Arastehfar, Farnaz Daneshnia, Nathaly Cabrera, Suyapa Penalva-Lopez, Jansy Sarathy, Matthew Zimmerman, Erika Shor () and David S. Perlin ()
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Amir Arastehfar: Hackensack Meridian Health
Farnaz Daneshnia: Hackensack Meridian Health
Nathaly Cabrera: Hackensack Meridian Health
Suyapa Penalva-Lopez: Hackensack Meridian Health
Jansy Sarathy: Hackensack Meridian Health
Matthew Zimmerman: Hackensack Meridian Health
Erika Shor: Hackensack Meridian Health
David S. Perlin: Hackensack Meridian Health

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Candida glabrata is a major fungal pathogen notable for causing recalcitrant infections, rapid emergence of drug-resistant strains, and its ability to survive and proliferate within macrophages. Resembling bacterial persisters, a subset of genetically drug-susceptible C. glabrata cells can survive lethal exposure to the fungicidal echinocandin drugs. Herein, we show that macrophage internalization induces cidal drug tolerance in C. glabrata, expanding the persister reservoir from which echinocandin-resistant mutants emerge. We show that this drug tolerance is associated with non-proliferation and is triggered by macrophage-induced oxidative stress, and that deletion of genes involved in reactive oxygen species detoxification significantly increases the emergence of echinocandin-resistant mutants. Finally, we show that the fungicidal drug amphotericin B can kill intracellular C. glabrata echinocandin persisters, reducing emergence of resistance. Our study supports the hypothesis that intra-macrophage C. glabrata is a reservoir of recalcitrant/drug-resistant infections, and that drug alternating strategies can be developed to eliminate this reservoir.

Date: 2023
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DOI: 10.1038/s41467-023-36882-6

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