Evidence map›Paper›PMID 42406593›Full record

ArticleCell reports2026

Plasmodium falciparum HSP90 inhibitors show divergent resistance despite a shared ATP-binding site.

Fu-Hsuan Ko, Amanda K Lukens, Mariana Laureano de Souza, Alex Foy, Jason Hsiao, Tolla Ndiaye, John Okombo, Tomas Yeo, Heekuk Park, Anne-Catrin Uhlemann and 14 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell reports, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing 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

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

24 authors.

Fu-Hsuan KoDivision of Biological Sciences, University of California, La Jolla, San Diego, CA, USA; Department of Pediatrics, University of California, San Diego, San Diego School of Medicine, La Jolla, San Diego, CA, USA.
Amanda K LukensInfectious Disease and Microbiome Program, The Broad Institute, Cambridge, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Mariana Laureano de SouzaDepartment of Pediatrics, University of California, San Diego, San Diego School of Medicine, La Jolla, San Diego, CA, USA.
Alex FoyDepartment of Pediatrics, University of California, San Diego, San Diego School of Medicine, La Jolla, San Diego, CA, USA.
Jason HsiaoDivision of Biological Sciences, University of California, La Jolla, San Diego, CA, USA; Department of Pediatrics, University of California, San Diego, San Diego School of Medicine, La Jolla, San Diego, CA, USA.
Tolla NdiayeDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA; Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
John OkomboDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA; Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
Tomas YeoDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA; Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
Heekuk ParkDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA; Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
Anne-Catrin UhlemannDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA; Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
Nonlawat BoonyalaiBiological Chemistry and Drug Discovery, Wellcome Centre for Anti-Infectives Research, University of Dundee, Dundee, UK.
Krittikorn KumpornsinWellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, UK.
Gareth GirlingWellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, UK.
Charisse PasajeDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Luiz GodoyDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Priyan KapoorDepartment of Pediatrics, University of California, San Diego, San Diego School of Medicine, La Jolla, San Diego, CA, USA; Department of Biological Engineering, University of California, La Jolla, San Diego, CA, USA.
Gregory L DurstLgenia Inc., Fortville, IN 46040, USA.
Sabine OttilieDepartment of Pediatrics, University of California, San Diego, San Diego School of Medicine, La Jolla, San Diego, CA, USA.
Arnab ChatterjeeScripps Research Institute, La Jolla, CA 92037, USA.
Jacquin NilesDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Marcus LeeBiological Chemistry and Drug Discovery, Wellcome Centre for Anti-Infectives Research, University of Dundee, Dundee, UK; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, UK.
David A FidockDepartment of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, USA; Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
Dyann F WirthInfectious Disease and Microbiome Program, The Broad Institute, Cambridge, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Elizabeth A WinzelerDepartment of Pediatrics, University of California, San Diego, San Diego School of Medicine, La Jolla, San Diego, CA, USA. Electronic address: ewinzeler@health.ucsd.edu.

Funding

Defining the resistome in P. falciparum: evolution and mechanismR01AI169892 · NIAID · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Daniel E. Goldberg, Elizabeth A Winzeler · 2023 to 2026
$4.4M
Defining the complex genetic basis of Plasmodium falciparum resistance to artemisinin and quinine and identifying resistance-refractory therapeuticsR01AI185559 · NIAID · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI David A Fidock · 2024 to 2026
$1.9M
Bill & Melinda Gates Foundation INV-033538NIAID NIH HHS R01 AI169892NIAID NIH HHS R01 AI185559
6 · The paper itself

Abstract

Drug resistance poses a major challenge across therapeutic areas including malaria, yet factors governing resistance propensity remain poorly understood. We demonstrate that two HSP90 inhibitors targeting the identical ATP-binding site exhibit dramatically different resistance profiles in P. falciparum. Geldanamycin readily selected 10 distinct resistance mutations conferring up to 22-fold resistance, while AUY-922 required 44 weeks to yield a single A41S mutation with only 2-fold resistance. Resistance mutations mapped throughout geldanamycin's binding pocket but localized near the ATP-binding site for AUY-922. Strikingly, A41S enhanced AUY-922 binding affinity via additional hydrogen bonding, yet stronger binding paradoxically correlated with resistance. Conditional HSP90 knockdown increased geldanamycin sensitivity but not AUY-922 activity, indicating distinct target dependencies despite shared binding sites. We propose AUY-922's lower resistance risk reflects engagement of multiple HSP90 family members. These findings demonstrate that resistance risk cannot be predicted from binding site identity alone, informing development of more durable therapeutics.

Indexed as

Adenosine TriphosphateDrug ResistanceHSP90 Heat-Shock ProteinsPlasmodium falciparumBenzoquinonesBinding SitesLactams, MacrocyclicMutationProtein BindingProtozoan ProteinsAdenosine TriphosphateBenzoquinonesgeldanamycinHSP90 Heat-Shock ProteinsLactams, MacrocyclicProtozoan ProteinsATP-binding siteAUY-922CP: microbiologydrug resistancegeldanamycinHSP90multi-target hypothesisPlasmodium falciparumresistance mutations

Identifiers

PMID42406593
PMCPMC13589290

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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.