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.

Bioinformatics Unit Department of Life Sciences Core Facilities Weizmann Institute of Science Rehovot Israel

Department of Chemical Research Support Weizmann Institute of Science Rehovot Israel

Department of Life Sciences Core Facilities Weizmann Institute of Science Rehovot Israel

École Polytechnique Fédérale de Lausanne Laboratory for Bio and Nano Instrumentation Lausanne Switzerland

Faculty of Biochemistry Department of Biomolecular Sciences Weizmann Institute of Science Rehovot Israel

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science Prague Czech Republic

Unité de Biologie de Plasmodium et Vaccins Institut Pasteur Université Paris Cité Paris France

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