Project Details

Ivermectin as a new paradigm for malaria: a synergistic bioassay evaluation

Carlos Chaccour, MD, MSc, PhD, DTM&H

Summary

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 set for 2030 by the World Health Organization. New tools will need to assess 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 potential approach has gained important attention, it is not free from potential development of resistance to ivermectin itself. The main aim of this work was to evaluate the potential role of xenobiotic pumps and cytochromes on ivermectin-induced mosquito mortality. We conducted an insectary-based randomized synergistic bioassay using membrane feeding to expose an Anopheles gambiae s.s to ivermectin with or without a battery of molecules affecting either the CYP3A4 or the P-glychoprotein. Seven drugs (or drug combinations) have been tested to assess the effect that the inhibition or induction of the said molecules can have on the ivermectin-caused mosquito mortality. In first place, dose-finding experiments were carried out to determine the 10-day LC 50 of ivermectin. This was followed by synergistic bioassays combining ivermectin with different concentrations of the additional drugs. The main outcome was 10 day mosquito mortality determined by daily manual accounts. Survival analysis was done by Log-Rank test and Cox’s regression. A dose-dependent synergism was found between ivermectin and CYP inhibitors like Voriconazole and Ritonavir. P-glychoprotein inducers did not show significant synergism. Other molecules like Cobicistat provided dose-dependent antagonism. Our data indicates that metabolic resistance to ivermectin could occur in the field. Website Link: https://www.isglobal.org/en/our-team/-/profiles/7304

Publications:

Nicolas P, Kiuru C, Wagah MG, Muturi M, Duthaler U, Hammann F, Maia M, Chaccour C. Potential metabolic resistance mechanisms to ivermectin in Anopheles gambiae: a synergist bioassay study. Parasit Vectors. 2021 Mar 20;14(1):172. doi: 10.1186/s13071-021-04675-9. PMID: 33743783; PMCID: PMC7981804.