Patricia Nicolas1,2, Caroline Kiuru1,2, Martin G Wagah3,4, Martha Muturi4, Urs Duthaler5,6, Felix Hammann7, Marta Maia4,8, Carlos Chaccour9,10,11. 1. ISGlobal, Hospital Clínic-Universitat de Barcelona, Rosello 132, 5ª 2ª, 08036, Barcelona, Spain. 2. Centro de Investigação em Saúde de Manhiça, 1929, Maputo, Mozambique. 3. Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 91SA, UK. 4. Department of Biosciences, KEMRI Wellcome Trust Research Programme, Kilifi, 230-80108, Kenya. 5. Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University and University Hospital Basel, 4056, Basel, Switzerland. 6. Division of Clinical Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of Basel, 4056, Basel, Switzerland. 7. Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, University Hospital Bern, 3010, Bern, Switzerland. 8. Nuffield Department of Medicine, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK. 9. ISGlobal, Hospital Clínic-Universitat de Barcelona, Rosello 132, 5ª 2ª, 08036, Barcelona, Spain. carlos.chaccour@isglobal.org. 10. Ifakara Health Institute, Ifakara, 67501, United Republic of Tanzania. carlos.chaccour@isglobal.org. 11. Facultad de Medicina, Universidad de Navarra, 31008, Pamplona, Spain. carlos.chaccour@isglobal.org.
Abstract
BACKGROUND: Despite remarkable success obtained with current malaria vector control strategies in the last 15 years, additional innovative measures will be needed to achieve the ambitious goals for malaria control set for 2030 by the World Health Organization (WHO). New tools will need to address insecticide resistance and residual transmission as key challenges. Endectocides such as ivermectin are drugs that kill mosquitoes which feed on treated subjects. Mass administration of ivermectin can effectively target outdoor and early biting vectors, complementing the still effective conventional tools. Although this approach has garnered attention, development of ivermectin resistance is a potential pitfall. Herein, we evaluate the potential role of xenobiotic pumps and cytochrome P450 enzymes in protecting mosquitoes against ivermectin by active efflux and metabolic detoxification, respectively. METHODS: We determined the lethal concentration 50 for ivermectin in colonized Anopheles gambiae; then we used chemical inhibitors and inducers of xenobiotic pumps and cytochrome P450 enzymes in combination with ivermectin to probe the mechanism of ivermectin detoxification. RESULTS: Dual inhibition of xenobiotic pumps and cytochromes was found to have a synergistic effect with ivermectin, greatly increasing mosquito mortality. Inhibition of xenobiotic pumps alone had no effect on ivermectin-induced mortality. Induction of xenobiotic pumps and cytochromes may confer partial protection from ivermectin. CONCLUSION: There is a clear pathway for development of ivermectin resistance in malaria vectors. Detoxification mechanisms mediated by cytochrome P450 enzymes are more important than xenobiotic pumps in protecting mosquitoes against ivermectin.
BACKGROUND: Despite remarkable success obtained with current malaria vector control strategies in the last 15 years, additional innovative measures will be needed to achieve the ambitious goals for malaria control set for 2030 by the World Health Organization (WHO). New tools will need to address insecticide resistance and residual transmission as key challenges. Endectocides such as ivermectin are drugs that kill mosquitoes which feed on treated subjects. Mass administration of ivermectin can effectively target outdoor and early biting vectors, complementing the still effective conventional tools. Although this approach has garnered attention, development of ivermectin resistance is a potential pitfall. Herein, we evaluate the potential role of xenobiotic pumps and cytochrome P450 enzymes in protecting mosquitoes against ivermectin by active efflux and metabolic detoxification, respectively. METHODS: We determined the lethal concentration 50 for ivermectin in colonized Anopheles gambiae; then we used chemical inhibitors and inducers of xenobiotic pumps and cytochrome P450 enzymes in combination with ivermectin to probe the mechanism of ivermectin detoxification. RESULTS: Dual inhibition of xenobiotic pumps and cytochromes was found to have a synergistic effect with ivermectin, greatly increasing mosquito mortality. Inhibition of xenobiotic pumps alone had no effect on ivermectin-induced mortality. Induction of xenobiotic pumps and cytochromes may confer partial protection from ivermectin. CONCLUSION: There is a clear pathway for development of ivermectin resistance in malaria vectors. Detoxification mechanisms mediated by cytochrome P450 enzymes are more important than xenobiotic pumps in protecting mosquitoes against ivermectin.
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Authors: Stephen R Manock; Ali Mtoro; Vicente Urbano Nsue Ndong; Ally Olotu; Mwajuma Chemba; Antonio E Sama Roca; Esther Eburi; Guillermo A García; Carlos Cortes Falla; Julie Niemczura de Carvalho; Jaime Contreras; Baltasar Saturno; Juan de Dios Riocalo; José Luis Nze Mba; Rima Koka; Seung Tae Lee; Hari Menon; L W Preston Church; Mitoha Ondo'o Ayekaba; Peter F Billingsley; Salim Abdulla; Thomas L Richie; Stephen L Hoffman Journal: Am J Trop Med Hyg Date: 2020-11-23 Impact factor: 2.345
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