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 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 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.

Ivermectin as a Novel Malaria Control Tool: Getting Ahead of the Resistance Curse

“…Yet, it does not bring the risk of emergence and spread of ivermectin resistance to zero since larvae, pupae and adult emergence have been reported (at low rates) in wild and laboratory Anopheles mosquitoes at a low concentration of ivermectin (75). isoenzymes (85)(86)(87).…”

“…Dual inhibition of xenobiotic pumps and P450 cytochromes was also found to greatly increase An. gambiae susceptibility to ivermectin, suggesting a clear pathway for development of ivermectin resistance by detoxification mechanisms (87). Alarmingly, permethrin-resistant cockroaches, houseflies, and Aedes aegypti have been shown to be less susceptible to abamectin or ivermectin when compared with permethrin-sensitive counterparts (91).…”

“…Since the PBO presents on these new generations of pyrethroid LLINs is intended to inhibit detoxification enzymes of resistant malaria vectors, mainly cytochrome P450 monooxygenases (116), this might be beneficial for ivermectin MDAs. Indeed, the inhibition of cytochrome P450 enzymes has been shown to increase the mortality of mosquitoes when the synergist is co-administered with the blood meal (87). Even though mosquitoes will not be taking a blood meal containing PBO, one could expect the pre or post exposure to PBO (through pyrethroid-PBO LLINs) to synergize with ivermectin and increase mosquito mortality.…”

“…gambiae mortality (87). In the case of ivermectin, some synergist may simultaneously work as pharmaco-enhancers, boosting both the systemic exposure and the mosquito susceptibility (136).…”