Evidence map›Paper›PMID 40624040›Full record

ArticleNature communications2025

Disruption of the ATP-dependent unfoldase ClpX reverses antifungal resistance in Cryptococcus neoformans.

M Woods, A Bermas, B Ball, B Muselius, N Chan, D Gutierrez-Gongora, S Ramezanpour, J A McAlister, S A Sieber, J Geddes-McAlister

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. Review
  3. Article
  4. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors.

M WoodsMolecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.
A BermasMolecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.
B BallMolecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.
B MuseliusMolecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.
N ChanMolecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.
D Gutierrez-GongoraMolecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.ORCID http://orcid.org/0000-0001-7972-3217
S RamezanpourMolecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.ORCID https://orcid.org/0000-0003-4972-2824
J A McAlisterMolecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.
S A SieberTUM School of Natural Sciences, Department Biosciences, Chair of Organic Chemistry II, Center for Functional Protein Assemblies (CPA), Technical University Munich (TUM), Garching, Germany.ORCID http://orcid.org/0000-0002-9400-906X
J Geddes-McAlisterMolecular and Cellular Biology, University of Guelph, Guelph, ON, Canada. jgeddesm@uoguelph.ca.ORCID http://orcid.org/0000-0002-4257-2096

Funding

Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Génie du Canada) Collaborative Research and Training Experience
6 · The paper itself

Abstract

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.

Indexed as

Antifungal AgentsCryptococcus neoformansDrug Resistance, FungalEndopeptidase ClpFungal ProteinsAdenosine TriphosphateAnimalsCryptococcosisErgosterolFluconazoleHumansMiceMicrobial Sensitivity TestsProteomicsAdenosine TriphosphateAntifungal AgentsEndopeptidase ClpErgosterolFluconazoleFungal Proteins

Identifiers

PMID40624040
PMCPMC12234750

What Socratic holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.