Year: 2025
Type: article
Abstract: The decline in malaria deaths has recently stalled owing to several factors, including the widespread resistance of Anopheles vectors to the insecticides used in long-lasting insecticide-treated nets (LLINs)1,2. One way to mitigate insecticide resistance is to directly kill parasites during their mosquito-stage of development by incorporating antiparasitic compounds into LLINs. This strategy can prevent onward parasite transmission even when insecticides lose efficacy3,4. Here, we performed an in vivo screen of compounds against the mosquito stages of Plasmodium falciparum development. Of the 81 compounds tested, which spanned 28 distinct modes of action, 22 were active against early parasite stages in the mosquito midgut lumen, which in turn prevented establishment of infection. Medicinal chemistry was then used to improve antiparasitic activity of the top hits from the screen. We generated several endochin-like quinolones (ELQs) that inhibited the P. falciparum cytochrome bc 1 complex (CytB). Two lead compounds that targeted separate sites in CytB (Qo and Qi) showed potent, long-lasting and stable activity when incorporated and/or extruded into bed net-like polyethylene films. ELQ activity was fully preserved in insecticide-resistant mosquitoes, and parasites resistant to these compounds had impaired development at the mosquito stage. These data demonstrate the promise of incorporating ELQ compounds into LLINs to counteract insecticide resistance and to reduce malaria transmission.
Source: Nature
Authors: Alexandra S. Probst, Douglas G. Paton, Federico Appetecchia, Selina Bopp, Kelsey L. Adams, Tasneem A. Rinvee, Sovitj Pou, Rolf Winter, Esrah W. Du, Sabrina Yahiya, Charles Vidoudez, Naresh Singh, Janneth Rodrigues, Pablo Castañeda-Casado, Chiara Tammaro, Daisy Chen, Karla P. Godinez-Macias, Jasmine L. Jaramillo, Giovanna Poce, Michael J. Rubal, Aaron Nilsen, Elizabeth A. Winzeler, Jake Baum, Jeremy N. Burrows, Michael K. Riscoe, Dyann F. Wirth, Flaminia Catteruccia
Institutions: Harvard University, University of Georgia, Portland VA Medical Center, Imperial College London, GlaxoSmithKline (Spain), Sapienza University of Rome, University of California San Diego, Southwest Research Institute, Oregon Health & Science University, UNSW Sydney, Medicines for Malaria Venture, Broad Institute, Howard Hughes Medical Institute
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: U.S. Department of Defense, Howard Hughes Medical Institute, U.S. Department of Veterans Affairs, GlaxoSmithKline, Office of Research and Development, Oregon Health and Science University, UK Research and Innovation, Open Philanthropy Project, Imperial College London, Medicines for Malaria Venture, National Institutes of Health, Directorate for Biological Sciences, University of California, San Diego, Biotechnology and Biological Sciences Research Council, National Institute of Allergy and Infectious Diseases
Awards: G1003731175, G1476237564, Graduate Training Program in Bioinformatics, Illumina NovaSeq 6000 Sequencing System, G3671069124, G3731947782, G4383540587, G4401027744, Development of a Sustained Release Injectable Formulation for Long-Term Delivery of ELQs, Determining the interactions between mosquito oogenesis and Plasmodium falciparum survival and transmission, G7550581054, G8085682287, Malaria transmission blocking through mosquito contact with treated surfaces, From bench to bednet: Developing novel mitochondrial inhibitors for killing Plasmodium in the malaria mosquito, The Graduate Program in Tropical Infectious Diseases, Novel Therapeutics to Target Parasite Cytochrome bc1
OpenAlex ID: W4410551306