| Title: |
Antimicrobial peptides selectively target malaria parasites by a cholesterol-dependent mechanism |
| Authors: |
Kiper, Edo; Ben Hur, Daniel; Alfandari, Daniel; Camacho, Abel Cruz; Wani, Naiem Ahmad; Efrat, Gal David; Morandi, Mattia; Goldsmith, Moshe; Rotkopf, Ron; Kamyshinsky, Roman; Deshmukh, Arunaditya; Binte Zulkifli, Nur Elyza; Asmari, Navid; Penedo, Marcos; Fantner, Georg; Porat, Ziv; Azuri, Ido; Rosenhek-Goldian, Irit; Chitnis, Chetan; Shai, Yechiel; Regev-Rudzki, Neta |
| Contributors: |
Weizmann Institute of Science Rehovot, Israël; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences (IOCB / CAS); Czech Academy of Sciences Prague (CAS); Biologie de plasmodium et vaccins - Malaria Parasite Biology and Vaccines; Institut Pasteur Paris (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité); Ecole Polytechnique Fédérale de Lausanne (EPFL); N. R. R. is funded by the European Union (European Research Council ERC , MalChemAtlas, 101086598). Views and opinions expressed by the author(s) do not necessarily reflect those of the European Union or the ERC. Neither the European Union nor the granting authority can be held responsible for them. N. R. R. is supported by the Minerva Program (grant number: 714142), by the Israel Science Foundation (ISF) (grant no.: 1637/20), within the Israel Precision Medicine Partnership program and the ISF (grant application no.: 570/21) and ISF—Canada-Israel Joint Health Research Program (IDRC, CIHR, and the Azrieli Foundation) (reference number: P141807). N. R. R. is deeply grateful for the support of the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics, the Dr. Barry Sherman Institute for Medicinal Chemistry, the Karen Siem Fellowship for Women in Science, the Brenden-Mann Women’s Innovation Impact Fund and Bina, the translational research and innovation unit of the Weizmann Institute. The research of Y. S. supported by the Israeli Ministry of Science and Technology (application no.: 3-14316) and the ISF (application no.: 1944/20). N. A., M. P., and G. E. F. acknowledge funding from the European Union H2020—UE Framework Programme for Research & Innovation (2014–2020); ERC-2017-CoG; InCell; project number: 773091. N. A., M. P., and G. E. F. acknowledge funding from the European Union H2020—UE Framework Programme for Research & Innovation (2014–2020); project number: 773091. |
| Source: |
ISSN: 0021-9258. |
| Publisher Information: |
CCSD; American Society for Biochemistry and Molecular Biology |
| Publication Year: |
2025 |
| Subject Terms: |
antimicrobial peptides; cholesterol-dependent mechanism; malaria; peptide–cytoskeleton interaction; peptide–membrane interaction; synthetic antimicrobial peptides; MESH: Plasmodium falciparum; MESH: Cholesterol; MESH: Humans; MESH: Antimalarials; MESH: Erythrocytes; MESH: Antimicrobial Peptides; MESH: Malaria; Falciparum; MESH: Animals; MESH: Antimicrobial Cationic Peptides; [SDV]Life Sciences [q-bio] |
| Description: |
International audience ; Hundreds of thousands die annually from malaria caused by Plasmodium falciparum (Pf), with the emergence of drug-resistant parasites hindering eradication efforts. Antimicrobial peptides (AMPs) are known for their ability to disrupt pathogen membranes without targeting specific receptors, thereby reducing the chance of drug resistance. However, their effectiveness and the biophysical mechanisms by which they target the intracellular parasite remain unexplored. Here, by using native and synthetic AMPs, we discovered a selective mechanism that underlies the antimalarial activity. Remarkably, the AMPs exclusively interact with Pf-infected red blood cells, disrupting the cytoskeletal network and reaching the enclosed parasites with correlation to their activity. Moreover, we showed that the unique feature of reduced cholesterol content in the membrane of the infected host makes Pf-infected red blood cells susceptible to AMPs. Overall, this work highlights the Achilles' heel of malaria parasite and demonstrates the power of AMPs as potential antimalarial drugs with reduced risk of resistance. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/39971158; PUBMED: 39971158; PUBMEDCENTRAL: PMC11993164 |
| DOI: |
10.1016/j.jbc.2025.108298 |
| Availability: |
https://u-paris.hal.science/hal-05123175; https://u-paris.hal.science/hal-05123175v1/document; https://u-paris.hal.science/hal-05123175v1/file/1-s2.0-S0021925825001462-main.pdf; https://doi.org/10.1016/j.jbc.2025.108298 |
| Rights: |
http://creativecommons.org/licenses/by-nc-nd/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.CD145127 |
| Database: |
BASE |