Novel Quinolones Counteract Insecticide Resistance in Malaria Vectors (May 2025)

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Novel Quinolones Counteract Insecticide Resistance in Malaria Vectors (May 2025)

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BRIEFING DOCUMENT: Novel Approach to Malaria Control Targeting Mosquito-Stage Plasmodium ParasitesDate: Received - 29 March 2025 | Accepted - 17 April 2025 | Published - 21 May 2025Source: Excerpts from "In vivo screen of Plasmodium targets for mosquito-based malaria control" by Probst et al. (Published online xx xx xxxx, Nature) https://doi.org/10.1038/s41586-025-09039-2Subject: Development and testing of novel antiparasitic compounds for incorporation into mosquito bed nets to combat insecticide resistance and reduce malaria transmission.Summary:This research presents a promising new strategy for malaria control by targeting the Plasmodium falciparum parasite directly within its mosquito vector (Anopheles species). Recognizing the growing challenge of insecticide resistance in mosquitoes, the study explores the potential of incorporating antiparasitic compounds into long-lasting insecticide-treated nets (LLINs). The authors performed an in vivo screen of 81 compounds, identifying 22 active against mosquito-stage parasites. Notably, endochin-like quinolones (ELQs) targeting the parasite's cytochrome bc1 complex (CytB) showed high potency and were further optimized through medicinal chemistry. Two lead ELQ compounds, ELQ-453 and ELQ-613, demonstrated potent, long-lasting activity when incorporated into bed net-like materials, including in insecticide-resistant mosquitoes. The study also highlights the potential of a dual-target strategy using a combination of Qo-site and Qi-site ELQ inhibitors to reduce the risk of resistance, as CytB mutants show impaired development in mosquitoes. This approach offers a complementary tool to existing malaria control strategies, particularly in areas with high insecticide resistance.Key Themes and Important Ideas/Facts:Malaria Burden and the Challenge of Insecticide Resistance:Malaria deaths have stalled in recent years, with an estimated 263 million cases and 597,000 deaths in 2023.Vector control, particularly LLINs, has been crucial in reducing malaria prevalence, but widespread insecticide resistance in Anopheles vectors is jeopardizing their effectiveness."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)..."Targeting Mosquito-Stage Parasites as a Mitigation Strategy:Directly killing parasites during their mosquito-stage development by incorporating antiparasitic compounds into LLINs can prevent onward transmission, even if insecticides lose efficacy.This strategy avoids conferring fitness costs or selective pressure on the mosquito, thus preventing vector resistance to the antiparasitic compound."Interventions that directly target parasites in the mosquito represent a promising approach to disrupt parasite transmission and to reduce malaria burden...""Of note, the use of a Plasmodium-specific compound would not confer any fitness cost or selective pressure to the anopheline mosquito, which therefore avoids potential development of resistance by the vector."In Vivo Compound Screening and Identification of Key Targets:An in vivo screen of 81 antiplasmodial compounds with diverse modes of action was performed in Anopheles gambiae mosquitoes.22 compounds spanning seven distinct P. falciparum targets significantly reduced parasite infection (oocyst prevalence) in the mosquito midgut.Key identified targets included the ubiquinol oxidation (Qo) and ubiquinone reduction (Qi) sites of the P. falciparum cytochrome bc1 complex (CytB), the sodium-proton antiporter P-type ATPase 4 (ATP4), and eukaryotic elongation factor 2 (EF2)."This screen ultimately identified 22 compounds that significantly reduced parasite infection, and these compounds spanned seven P. falciparum targets..."Endochin-Like Quinolones (ELQs) as Lead Compounds:Endochin-like quinolones (ELQs) targeting CytB were among the most effective compounds in the topical screen.ELQ-456 (targeting the CytB Qo-site) completely inhibited infection in topical applications.ELQ-331 (targeting the CytB Qi-site) strongly reduced infection prevalence.Medicinal chemistry was used to improve the antiparasitic activity of ELQ hits, particularly for uptake via tarsal contact (mosquito legs).Tarsal Contact Activity and the Importance of Compound Structure:Tarsal contact assays, mimicking mosquito interaction with treated surfaces like bed nets, showed that most compounds active in topical application were inactive.Only ELQ-456 initially showed significant activity in tarsal contact assays.Modifications to the ELQ structure significantly enhanced tarsal-based efficacy. ELQ-453 (Qo-site inhibitor) and ELQ-613 (Qi-site inhibitor), with specific alkyl chain lengths, demonstrated potent activity after tarsal contact."Of the 13 compounds we tested in tarsal-contact assays, only our most potent hit in the topical screen, ELQ-456 (CytB Qo-site inhibitor) reduced infection (69.5% ...