Evidence map›Paper›PMID 41478284›Full record

ArticleCell2026

Butyrolactol A enhances caspofungin efficacy via flippase inhibition in drug-resistant fungi.

Xuefei Chen, H Diessel Duan, Michael J Hoy, Kalinka Koteva, Michaela Spitzer, Allison K Guitor, Emily Puumala, Aline A Fiebig, Guanggan Hu, Bonnie Yiu and 18 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.

0numbers the graph read from it
0cells of the map it votes in
14citing papers in PubMed
–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

14 citing papers in PubMed.

  1. Review
  2. Review
  3. Article
  4. Article
  5. Article
  6. Innovation in antifungal therapy.EMBO molecular medicine · 2026
    Review
  7. Natural Killer Cells: Dual Regulators and Therapeutic Targets in Multiple Sclerosis Immunopathogenesis.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2026
    Review
  8. Flipping the drug resistance switch.Nature reviews. Microbiology · 2026
    Article
  9. Article
  10. Review
  11. Review
  12. Inheriting chromosome conformation.Nature cell biology · 2026
    Article
  13. Article
  14. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

28 authors.

Xuefei ChenDavid Braley Centre for Antibiotics Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
H Diessel DuanDepartment of Structural Biology, Van Andel Institute, Grand Rapids, MI 49503, USA.
Michael J HoyDepartment of Molecular Genetics and Microbiology, Duke University, Duke University Medical Center, Durham, NC 27710, USA.
Kalinka KotevaDavid Braley Centre for Antibiotics Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
Michaela SpitzerDavid Braley Centre for Antibiotics Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
Allison K GuitorDavid Braley Centre for Antibiotics Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
Emily PuumalaDepartment of Molecular Genetics, University of Toronto, Toronto, ON M5G 1M1, Canada.
Aline A FiebigDavid Braley Centre for Antibiotics Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
Guanggan HuMichael Smith Laboratories, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.
Bonnie YiuDepartment of Molecular Genetics, University of Toronto, Toronto, ON M5G 1M1, Canada.
Sommer ChouDavid Braley Centre for Antibiotics Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
Zhuyun BianDepartment of Molecular Genetics and Microbiology, Duke University, Duke University Medical Center, Durham, NC 27710, USA.
Yeseul ChoiDepartment of Molecular Genetics and Microbiology, Duke University, Duke University Medical Center, Durham, NC 27710, USA.
Amelia Bing Ya GuoDavid Braley Centre for Antibiotics Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
Wenliang WangDavid Braley Centre for Antibiotics Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
Sheng SunDepartment of Molecular Genetics and Microbiology, Duke University, Duke University Medical Center, Durham, NC 27710, USA.
Nicole RobbinsDepartment of Molecular Genetics, University of Toronto, Toronto, ON M5G 1M1, Canada.
Anna Floyd AveretteDepartment of Molecular Genetics and Microbiology, Duke University, Duke University Medical Center, Durham, NC 27710, USA.
Michael A CookDavid Braley Centre for Antibiotics Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
Ray TruantDepartment of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada.
Lesley T MacNeilDavid Braley Centre for Antibiotics Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada.
Eric D BrownDavid Braley Centre for Antibiotics Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
James W KronstadMichael Smith Laboratories, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.
Brian K CoombesDavid Braley Centre for Antibiotics Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
Leah E CowenDepartment of Molecular Genetics, University of Toronto, Toronto, ON M5G 1M1, Canada.
Joseph HeitmanDepartment of Molecular Genetics and Microbiology, Duke University, Duke University Medical Center, Durham, NC 27710, USA.
Huilin LiDepartment of Structural Biology, Van Andel Institute, Grand Rapids, MI 49503, USA. Electronic address: huilin.li@vai.org.
Gerard D WrightDavid Braley Centre for Antibiotics Discovery, M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada. Electronic address: wrightge@mcmaster.ca.

Funding

Structure, function, and evolution of the Cryptococcus MAT locusR01AI050113 · NIAID · DUKE UNIVERSITY · PI HEITMAN, JOSEPH · 2002 to 2024
$8.5M
ROLE OF CALCINEURIN IN C. NEOFORMANS MATING AND FRUITINGR01AI039115 · NIAID · DUKE UNIVERSITY · PI HEITMAN, JOSEPH · 1997 to 2025
$6.7M
Comparative and functional genomics of C. neoformansR01AI053721 · NIAID · UNIVERSITY OF BRITISH COLUMBIA · PI KRONSTAD, JAMES W · 2003 to 2024
$5.4M
Systematic Analysis of Morphogenesis, Commensalism, and Virulence in a Leading Human Fungal PathogenR01AI127375 · NIAID · UNIVERSITY OF TORONTO · PI LEAH Elizabeth Cowen · 2017 to 2026
$5.3M
Genetics of Cryptococcus sexual reproductionR37AI039115 · NIAID · DUKE UNIVERSITY · PI HEITMAN, JOSEPH · 2011 to 2020
$4.9M
The Genetic Basis of Virulence in Cryptococcus NeoformansR01AI133654 · NIAID · DUKE UNIVERSITY · PI JOSEPH HEITMAN, Paul Mitaari Magwene · 2017 to 2026
$4.7M
The structure and function of eukaryotic protein glycosylation enzymesR01CA231466 · NCI · VAN ANDEL RESEARCH INSTITUTE · PI Huilin Li · 2018 to 2026
$4.0M
RNAi-dependent epimutation roles in antimicrobial drug resistance and pathogenesisR01AI170543 · NIAID · DUKE UNIVERSITY · PI JOSEPH HEITMAN · 2022 to 2026
$3.6M
Calcineurin signaling cascades governing Cryptococcus virulenceR01AI172451 · NIAID · DUKE UNIVERSITY · PI JOSEPH HEITMAN · 2023 to 2026
$2.7M
Structure-guided development of fungal specific calcineurin inhibitorsF31AI150120 · NIAID · DUKE UNIVERSITY · PI HOY, MICHAEL · 2020 to 2021
$76k
NCI NIH HHS R01 CA231466NIAID NIH HHS F31 AI150120NIAID NIH HHS R01 AI039115NIAID NIH HHS R01 AI050113NIAID NIH HHS R01 AI053721NIAID NIH HHS R01 AI127375NIAID NIH HHS R01 AI133654NIAID NIH HHS R01 AI170543NIAID NIH HHS R01 AI172451NIAID NIH HHS R37 AI039115
6 · The paper itself

Abstract

Fungal infections cause millions of deaths annually and are challenging to treat due to limited therapeutic options and rising resistance. Cryptococci are intrinsically resistant to the latest generation of antifungals, echinocandins, while Candida auris, a notorious global threat, is also increasingly resistant. We performed a natural product screen to rescue caspofungin fungicidal activity against Cryptococcus neoformans H99 and identified butyrolactol A, which restores echinocandin efficacy against resistant fungal pathogens, including multidrug-resistant C. auris. Mode-of-action studies reveal that butyrolactol A inhibits the phospholipid flippase Apt1-Cdc50, blocking phospholipid transport. Cryo-electron microscopy analysis of the Apt1-butyrolactol A complex reveals that the flippase is trapped in a dead-end state. Apt1 inhibition disrupts membrane asymmetry, vesicular trafficking, and cytoskeletal organization, thereby enhancing echinocandin uptake and potency. This study identifies lipid flippases as promising antifungal targets and demonstrates the potential of revisiting natural products to expand the antifungal arsenal and combat resistance.

Indexed as

Antifungal AgentsCaspofunginCryptococcus neoformansDrug Resistance, FungalCandida aurisCryoelectron MicroscopyEchinocandinsFungal ProteinsMicrobial Sensitivity TestsAntifungal AgentsCaspofunginEchinocandinsFungal ProteinsantifungalApt1-Cdc50butyrolactol ACandida aurisCryptococcusechinocandinflippasefungal resistancenatural productsynergy

Identifiers

PMID41478284
PMCPMC12774453

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Registered trials

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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 OpenQuestion graph.