Evidence map›Paper›PMID 41061700›Full record

ArticleCell chemical biology2025

Disruption of P. falciparum amino acid transporter elevates intracellular proline and induces resistance to Prolyl-tRNA synthetase inhibitors.

Selina Bopp, Lọla Fagbami, Amy Deik, Claudia Taccheri, Akansha Pant, Madeline Luth, Daisy Chen, Mark A Tye, Imran Ullah, Johannes Kreuzer and 7 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell chemical biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing 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

3 citing papers in PubMed.

  1. Article
  2. Article
  3. PfApiAT2 is a proline transporter essential for the transmission ofbioRxiv : the preprint server for biology · 2026
    Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

17 authors.

Selina BoppDepartment of Immunology and Infectious Diseases, Harvard T. H Chan School of Public Health, Boston, MA 02115, USA.
Lọla FagbamiDepartment of Immunology and Infectious Diseases, Harvard T. H Chan School of Public Health, Boston, MA 02115, USA.
Amy DeikMetabolomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Claudia TaccheriDepartment of Immunology and Infectious Diseases, Harvard T. H Chan School of Public Health, Boston, MA 02115, USA.
Akansha PantDepartment of Immunology and Infectious Diseases, Harvard T. H Chan School of Public Health, Boston, MA 02115, USA.
Madeline LuthDivision of Host Microbe Systems and Therapeutics, Department of Pediatrics, University of California, San Diego (UCSD), La Jolla, CA 92123, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Daisy ChenDivision of Host Microbe Systems and Therapeutics, Department of Pediatrics, University of California, San Diego (UCSD), La Jolla, CA 92123, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Mark A TyeCenter for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Graduate School of Arts and Sciences, Cambridge, MA 02138, USA.
Imran UllahDepartment of Immunology and Infectious Diseases, Harvard T. H Chan School of Public Health, Boston, MA 02115, USA.
Johannes KreuzerMassachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA.
Robert MorrisMassachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA.
Wilhelm HaasMassachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA.
Elizabeth A WinzelerDivision of Host Microbe Systems and Therapeutics, Department of Pediatrics, University of California, San Diego (UCSD), La Jolla, CA 92123, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Clary ClishMetabolomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Amanda K LukensDepartment of Immunology and Infectious Diseases, Harvard T. H Chan School of Public Health, Boston, MA 02115, USA; Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Ralph MazitschekDepartment of Immunology and Infectious Diseases, Harvard T. H Chan School of Public Health, Boston, MA 02115, USA; Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Dyann F WirthDepartment of Immunology and Infectious Diseases, Harvard T. H Chan School of Public Health, Boston, MA 02115, USA; Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: dfwirth@hsph.harvard.edu.

Funding

Training Program in Basic Clinical GeneticsT32GM008666 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI HAMILTON, BRUCE A · 1998 to 2021
$8.6M
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
Proline homeostasis: a novel mediator of drug tolerance in Plasmodium falciparumR01AI143723 · NIAID · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · PI MAZITSCHEK, RALPH, WIRTH, DYANN F · 2020 to 2024
$3.4M
Inhibitor class dependent consequences of prolyl-tRNA synthetase inhibition in Plasmodium falciparumR21AI132981 · NIAID · MASSACHUSETTS GENERAL HOSPITAL · PI MAZITSCHEK, RALPH · 2017 to 2018
$470k
Characterizing the Plasmodium falciparum Apicomplexan amino acid transporter 2 and its proline transport capabilityR21AI182540 · NIAID · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · PI Selina Bopp · 2025 to 2026
$443k
Chemogenomic Interrogation of Non-Genetic Drug Resistance in Plasmodium falciparumF31AI129412 · NIAID · HARVARD SCHOOL OF PUBLIC HEALTH · PI FAGBAMI, OLUFUNBI DAMILOLA · 2017 to 2018
$70k
NIAID NIH HHS F31 AI129412NIAID NIH HHS R01 AI143723NIAID NIH HHS R01 AI169892NIAID NIH HHS R21 AI132981NIAID NIH HHS R21 AI182540NIGMS NIH HHS T32 GM008666
6 · The paper itself

Abstract

Plasmodium falciparum evades the antimalarial activity of proline-competitive prolyl-tRNA synthetase (PfProRS) inhibitors, such as halofuginone (HFG), by a resistance mechanism termed the adaptive proline response (APR). The APR is characterized by a marked elevation of intracellular proline following drug exposure. Contrary to initial expectations, the APR is not mediated by alterations in canonical proline metabolic pathways involving arginase (P. falciparum arginase [PfARG]) and ornithine aminotransferase (P. falciparum ornithine aminotransferase [PfOAT]). Instead, we identified loss-of-function mutations in the apicomplexan amino acid transporter 2 (P. falciparum apicomplexan amino acid transporter 2 [PfApiAT2]) as the primary genetic driver of this resistance phenotype. Importantly, reversion of these mutations to wild type effectively suppresses the APR, establishing PfApiAT2 as the molecular determinant of this resistance mechanism. The elucidation of the APR significantly advances our understanding of antimalarial drug resistance. By delineating the role of PfApiAT2 in this process, we establish critical insights for the development of strategies to circumvent PfProRS inhibitor resistance for future antimalarial therapies.

Indexed as

Amino Acyl-tRNA SynthetasesAntimalarialsDrug ResistanceEnzyme InhibitorsPlasmodium falciparumProlineProtozoan ProteinsHumansPiperidinesQuinazolinonesAmino Acyl-tRNA SynthetasesAntimalarialsEnzyme InhibitorshalofuginonePiperidinesProlineprolyl T RNA synthetaseProtozoan ProteinsQuinazolinonesadaptive proline responseapicomplexan amino acid transporterdrug resistancehalofuginonemalariaPlasmodium falciparumprolyl-tRNA synthetase

Identifiers

PMID41061700
PMCPMC12997256

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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.