Potential metabolic resistance mechanisms to ivermectin in Anopheles gambiae: a synergist bioassay study

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.

Proof-of-concept study for a long-acting formulation of ivermectin injected in cattle as a complementary malaria vector control tool

“…Among all the formulations that have been tested so far, ours offers the unique advantage of being injected in a single shot and of progressive resorption while releasing active concentrations of ivermectin for a duration that could largely encompass the Plasmodium transmission season. The LC 50 values found in our study were in the same range as previous in vivo experiments reports [ 41 , 47 , 48 ], and are compatible with the therapeutic effects of ivermectin for the treatment of parasitic diseases in humans and animals [ 47 ]. For these reasons, the concept of an injectable long-acting formulation of ivermectin appears to be an effective tool to combat malaria transmission through a mass treatment of cattle, and ultimately of all domesticated animals that are hosts for Anopheles vectors.…”

“…Whatever the formulation, administering ivermectin to animals will require further studies to consider the risk of ivermectin resistance in the populations of helminths that are classically treated using ivermectin [ 49 ], but also, in Anopheles populations [ 48 ]. The selection pressure exerted by ivermectin will increase dramatically if the approach is deployed on a mass scale, and the emergence of ivermectin resistance would likely be only a matter of time, as has been the case for all other insecticidal compounds widely used to date.…”

A field bioassay for assessing ivermectin bio-efficacy in wild malaria vectors

“…A colony of Anopheles gambiae s.s. (Kili strain) maintained at KEMRI-Wellcome Trust Research Programme insectary was used in this study [21]. The colony undergoes biannual insecticide resistance monitoring using the WHO tube tests.…”

Effects of larval exposure to sublethal doses of ivermectin on adult fitness and susceptibility to ivermectin in Anopheles gambiae s.s.

“…Adult mosquitoes emerging from larvae exposed to ivermectin were placed in 1 Litre mosquito holding cups previously described in [17]. The mosquitoes were starved for 5 hours before being membrane-fed on blood spiked with ivermectin at a concentration of 11ng/ml.…”