Related Experiment Video
Updated: May 27, 2025
Author Spotlight: Identifying Compensatory Pathways in Malaria Parasites Containing Hypomorphic Allele of Essential Protein Kinases
Published on: November 22, 2024
Antimicrobial peptides selectively target malaria parasites by a cholesterol-dependent mechanism
Edo Kiper1, Daniel Ben Hur1, Daniel Alfandari1
1Faculty of Biochemistry, Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.
Abstract:
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.
Insights
Antimicrobial peptides (AMPs) show promise against malaria by targeting Plasmodium falciparum (Pf)-infected red blood cells. Their unique mechanism exploits reduced cholesterol in infected cells, offering a new drug strategy with low resistance risk.
Area of Science:
- Biochemistry
- Parasitology
- Drug Discovery
Background:
- Malaria, caused by Plasmodium falciparum (Pf), leads to hundreds of thousands of deaths annually.
- Emerging drug resistance in Pf parasites complicates malaria eradication efforts.
- Antimicrobial peptides (AMPs) offer a potential alternative due to their membrane-disrupting mechanism, reducing resistance risk.
Purpose of the Study:
- To investigate the effectiveness and biophysical mechanisms of AMPs against the intracellular malaria parasite.
- To explore the selective targeting of Pf-infected red blood cells by AMPs.
- To identify host-parasite interactions exploitable for antimalarial drug development.
Main Methods:
- Utilized native and synthetic antimicrobial peptides (AMPs).
- Examined the interaction of AMPs with Plasmodium falciparum (Pf)-infected red blood cells.
- Analyzed the biophysical properties of infected host cell membranes, specifically cholesterol content.
- Assessed the disruption of the host cell cytoskeleton and parasite accessibility.
Main Results:
- AMPs selectively interact with Pf-infected red blood cells, not healthy ones.
- Disruption of the infected red blood cell cytoskeletal network facilitates parasite access.
- Reduced cholesterol content in the membrane of infected host cells is a key factor for AMP susceptibility.
- A strong correlation was observed between AMP activity and their ability to reach the intracellular parasite.
Conclusions:
- Antimicrobial peptides (AMPs) possess a selective antimalarial mechanism targeting Plasmodium falciparum (Pf).
- The unique biophysical properties of infected host cells, specifically lower cholesterol, represent an Achilles' heel for the parasite.
- AMPs demonstrate significant potential as antimalarial drugs with a reduced risk of resistance development.
