Collateral sensitivity counteracts the evolution of antifungal drug resistance in Candida auris

Antifungal drug resistance represents a serious global health threat, necessitating new treatment strategies. Here we investigated collateral sensitivity (CS), in which resistance to one drug increases sensitivity to another, and cross-resistance (XR), in which one drug resistance mechanism reduces...

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Bibliographic Details
Published in:	Nature microbiology Vol. 9; no. 11; pp. 2954 - 2969
Main Authors:	Carolus, Hans, Sofras, Dimitrios, Boccarella, Giorgio, Jacobs, Stef, Biriukov, Vladislav, Goossens, Louise, Chen, Alicia, Vantyghem, Ina, Verbeeck, Tibo, Pierson, Siebe, Lobo Romero, Celia, Steenackers, Hans, Lagrou, Katrien, van den Berg, Pieter, Berman, Judith, Gabaldón, Toni, Van Dijck, Patrick
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-11-2024 Nature Publishing Group
Subjects:	42/70 45/47 631/181/2475 631/326/193/2540 631/326/22/1292 631/326/22/1434 692/699/255/1672 Antifungal agents Antifungal Agents - pharmacology Biomedical and Life Sciences Candida - drug effects Candida - genetics Candida auris Candida auris - drug effects Candida auris - genetics Candidiasis - drug therapy Candidiasis - microbiology Cross-resistance Decision making Drug development Drug resistance Drug Resistance, Fungal Evolution Humans Infectious Diseases Life Sciences Mathematical models Medical Microbiology Microbial Sensitivity Tests Microbiology Models, Theoretical Parasitology Population dynamics Public health Virology
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Summary:	Antifungal drug resistance represents a serious global health threat, necessitating new treatment strategies. Here we investigated collateral sensitivity (CS), in which resistance to one drug increases sensitivity to another, and cross-resistance (XR), in which one drug resistance mechanism reduces susceptibility to multiple drugs, since CS and XR dynamics can guide treatment design to impede resistance development, but have not been systematically explored in pathogenic fungi. We used experimental evolution and mathematical modelling of Candida auris population dynamics during cyclic and combined drug exposures and found that especially CS-based drug cycling can effectively prevent the emergence of drug resistance. In addition, we found that a CS-based treatment switch can actively select against or eradicate resistant sub-populations, highlighting the potential to consider CS in therapeutic decision-making upon resistance detection. Furthermore, we show that some CS trends are robust among different strains and resistance mechanisms. Overall, these findings provide a promising direction for improved antifungal treatment approaches. Collateral-sensitivity-based drug cycling effectively prevents and impedes the evolution of antifungal drug resistance in Candida auris .
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2058-5276 2058-5276
DOI:	10.1038/s41564-024-01811-w