Asset Details
Do you wish to reserve the book?
Disruption of the ATP-dependent unfoldase ClpX reverses antifungal resistance in Cryptococcus neoformans
Hey, we have placed the reservation for you!
By the way, why not check out events that you can attend while you pick your title.
Oops! Something went wrong.
Looks like we were not able to place the reservation. Kindly try again later.
Are you sure you want to remove the book from the shelf?
Disruption of the ATP-dependent unfoldase ClpX reverses antifungal resistance in Cryptococcus neoformans
Do you wish to request the book?
Disruption of the ATP-dependent unfoldase ClpX reverses antifungal resistance in Cryptococcus neoformans
Please be aware that the book you have requested cannot be checked out. If you would like to checkout this book, you can reserve another copy
We have requested the book for you!
Your request is successful and it will be processed during the Library working hours. Please check the status of your request in My Requests.
Oops! Something went wrong.
Looks like we were not able to place your request. Kindly try again later.
Journal Article
Disruption of the ATP-dependent unfoldase ClpX reverses antifungal resistance in Cryptococcus neoformans
2025
Overview
Fungal diseases impact the lives of a millions of people across the globe, and with our current repertoire of therapeutic options dwindling, effective treatment strategies are urgently needed. Critically, the emergence of azole-resistant isolates in the clinic following prolonged treatment regimes, environmental fungicide exposure, and fungal evolution, threatens the outcome of current therapeutics, further endangering the survival of infected individuals. Here, we investigate the underpinnings of antifungal resistance using quantitative proteomics to discover protein-level signatures of fluconazole (FLC) resistance in the opportunistic human fungal pathogen,
Cryptococcus neoformans
. We explore ClpX, an ATP-dependent unfoldase, as a target to overcome FLC resistance and explore target efficacy through macrophage and murine models of cryptococcal infection. Here we show that disruption of ClpX, following gene deletion or targeted inhibition, re-introduces FLC susceptibility into resistant strains, rendering FLC treatment effective once again. Further, we identify and experimentally confirm mechanisms by which ClpX influences susceptibility to FLC, through association with both heme biosynthesis and ergosterol production. Overall, our results contribute to the understanding of mechanisms driving FLC resistance in a globally important fungal pathogen, and we provide avenues for targeting proteins as a therapeutic strategy to reverse antifungal resistance.
Here, the authors reveal that the ATP-dependent unfoldase ClpX is a key driver of fluconazole resistance in
Cryptococcus neoformans
, and show that targeting ClpX restores drug susceptibility, offering a potential therapeutic strategy to reverse antifungal resistance and to render current drugs effective.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 64
/ 82/58
/ Adenosine Triphosphate - metabolism
/ Animals
/ Antifungal Agents - pharmacology
/ Cryptococcosis - drug therapy
/ Cryptococcosis - microbiology
/ Cryptococcus neoformans - drug effects
/ Cryptococcus neoformans - enzymology
/ Cryptococcus neoformans - genetics
/ Cryptococcus neoformans - metabolism
/ Drug Resistance, Fungal - drug effects
/ Drug Resistance, Fungal - genetics
/ Endopeptidase Clp - genetics
/ Endopeptidase Clp - metabolism
/ Fungal Proteins - metabolism
/ Fungi
/ Humanities and Social Sciences
/ Humans
/ Mice
/ Principal components analysis
/ Proteins
/ Science
/ Trends
