Evidence map›Paper›PMID 40432501›Full record

ArticleThe Journal of antimicrobial chemotherapy2025

Inner-mitochondrial membrane protein PfMPV17 is linked to P. falciparum in vitro resistance to the indoloquinolizidine alkaloid alstonine.

J R Macdonald, M S Arnold, M R Luth, D Cihalova, R J Quinn, E A Winzeler, M C Lee, G G van Dooren, A G Maier, T S Skinner-Adams and 2 more

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Article in The Journal of antimicrobial chemotherapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0citing papers in PubMed
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1 · What the graph read from it

What it found

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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

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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

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5 · Who and what money

Authors and funding

12 authors.

J R MacdonaldInstitute for Biomedicine and Glycomics, Griffith University, Brisbane, Queensland, Australia.
M S ArnoldInstitute for Biomedicine and Glycomics, Griffith University, Brisbane, Queensland, Australia.
M R LuthDepartment of Pediatrics, University of California, San Diego, USA.
D CihalovaResearch School of Biology, Australian National University, Canberra, ACT, Australia.
R J QuinnInstitute for Biomedicine and Glycomics, Griffith University, Brisbane, Queensland, Australia.
E A WinzelerDepartment of Pediatrics, School of Medicine, and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, USA.
M C LeeDivision of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.
G G van DoorenResearch School of Biology, Australian National University, Canberra, ACT, Australia.
A G MaierResearch School of Biology, Australian National University, Canberra, ACT, Australia.
T S Skinner-AdamsInstitute for Biomedicine and Glycomics, Griffith University, Brisbane, Queensland, Australia.
K T AndrewsInstitute for Biomedicine and Glycomics, Griffith University, Brisbane, Queensland, Australia.
G M FisherInstitute for Biomedicine and Glycomics, Griffith University, Brisbane, Queensland, Australia.

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
Discovery of long-acting, chemoprotective antimalarial compoundsR01AI152533 · NIAID · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI WINZELER, ELIZABETH A · 2020 to 2024
$3.5M
Bill & Melinda Gates Foundation 1R01AI152533Bill & Melinda Gates Foundation INV-039628Commonwealth Government Research Training programmeGriffith University GRIDD ECRGriffith University Postgraduate Research ScholarshipNational Health and Medical Research Council GNT1182369National Institute for General Medical Sciences T32 GM008666MRLNIAID NIH HHS R01 AI152533NIAID NIH HHS R01 AI169892NIGMS NIH HHS T32 GM008666NIH HHSRuth L. Kirschstein Institutional National Research Award
6 · The paper itself

Abstract

backgroundThere are an estimated 260 million malaria cases and ∼600 000 deaths annually. Challenges to malaria eradication include the lack of highly effective and broadly applicable vaccines and parasite drug resistance. This is driving the need for new tools, including novel drugs and drug targets. The indoloquinolizidine alkaloid alstonine was previously shown to have in vitro activity against Plasmodium falciparum malaria parasites and a slow-action activity that is different from other slow-action antiplasmodial compounds such as clindamycin.

objectivesTo investigate the action of the antiplasmodial compound alstonine by validating a putative resistance mutation and determining whether the activity of alstonine is linked to the mitochondrial electron transport chain. MATERIALS AND

methodsIn vitro evolution of resistance was used to generate alstonine-resistant P. falciparum, followed by whole-genome sequencing and CRISPR/Cas9 gene editing of wildtype parasites to validate a putative resistance-associated mutation. Links to mitochondrial function were assessed using oxygen consumption rate measurements and activity of alstonine in P. falciparum expressing the yeast dihydroorotate dehydrogenase.

resultsP. falciparum parasites were selected with ∼20-fold reduced sensitivity to alstonine compared to wild-type parasites. Whole-genome sequencing of alstonine-resistant P. falciparum sub-clones identified several mutations including a copy number variation and point mutation (A318P) in a gene encoding a putative inner-mitochondrial membrane protein (PfMPV17). Introduction of the A318P mutation into the PfMPV17 gene in wild-type P. falciparum yielded parasites with reduced alstonine sensitivity. While a direct link between alstonine action and mitochondrial respiratory function was not found, a transgenic P. falciparum line resistant to the cytochrome bc1 inhibitor atovaquone and pyrimidine synthesis inhibitor DSM265 had reduced sensitivity to alstonine.

conclusionsThese data demonstrate that PfMPV17 is linked to alstonine resistance and suggest that alstonine action is linked to the mitochondria and/or pyrimidine biosynthesis pathways.

Indexed as

AntimalarialsDrug ResistanceMitochondrial ProteinsPlasmodium falciparumProtozoan ProteinsQuinolizidinesAlkaloidsHumansMitochondriaMutationWhole Genome SequencingAlkaloidsAntimalarialsMitochondrial ProteinsProtozoan ProteinsQuinolizidines

Identifiers

PMID40432501
PMCPMC12209839

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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.