A natural agonist of mosquito TRPA1 from the medicinal plant Cinnamosma fragrans that is toxic, antifeedant, and repellent to the yellow fever mosquito Aedes aegypti

Abstract

Plants produce various secondary metabolites that offer a potential source of novel insecticides and repellents for the control of mosquito vectors. Plants of the genus Cinnamosma are endemic to, and widely-distributed throughout, the island of Madagascar. The barks of these species are commonly used in traditional medicines for treating a wide range of maladies. The therapeutic nature of the bark is thought to be associated with its enrichment of pungent drimane sesquiterpenes, which elicit antifeedant and toxic effects in some insects. Here we test the hypothesis that a bark extract of Cinnamosma fragrans (CINEX) and its major drimane sesquiterpenes are insecticidal, antifeedant, and repellent to Aedes aegypti, the principal mosquito vector of chikungunya, dengue, yellow fever, and Zika viruses. We demonstrate that CINEX is 1) toxic to larval and adult female mosquitoes, and 2) antifeedant and repellent to adult female mosquitoes. Moreover, we show that cinnamodial (CDIAL), a sesquiterpene dialdehyde isolated from CINEX, duplicates these bioactivities and exhibits similar toxic potency against pyrethroid-susceptible and -resistant strains of Ae. aegypti. Importantly, we show that CDIAL is an agonist of heterologously-expressed mosquito Transient Receptor Potential A1 (TRPA1) channels, and the antifeedant activity of CDIAL is dampened in a TRPA1-deficient strain of Ae. aegypti (TRPA1-/-). Intriguingly, TRPA1-/- mosquitoes do not exhibit toxic resistance to CDIAL. The data indicate that modulation of TRPA1 is required for the sensory detection and avoidance of CDIAL by mosquitoes, but not for inducing the molecule’s toxicity. Our study suggests that CDIAL may serve as a novel chemical platform for the development of natural product-based insecticides and repellents for controlling mosquito vectors.

Semi-synthetic Cinnamodial Analogues: Structural Insights into the Insecticidal and Antifeedant Activities of Drimane Sesquiterpenes Against the Mosquito Aedes aegypti

“…Unsaturated dialdehydecontaining compounds exhibit diverse bioactivities 23,24 , including antimicrobial 25 , antifungal 25 , molluscicidal 26 , and cytoxicity 27 . Additionally compounds 1, 2 and 3 are pungent to humans [28][29][30] , possess antifeedant and insecticidal activity 31,32 , and agonize Transient Receptor Potential A1 (TRPA1) channels 21,22,30,33,34 . Most biological activities, including the antifeedant activity, of these drimane sesquiterpenes have been attributed to the α,β-unsaturated 1,4-dialdehyde functionality of the molecules, forming adducts with free sulfhydryl groups 35,36 or primary amines such as the ε-amino group of lysine 37,38 .…”

“…All prepared CDIAL derivatives were screened for 24 h larvicidal activity against 1 st instar Ae. aegypti (Liverpool, LVP, strain) using a concentration of 100 µM in the rearing water 21 . At this concentration, CDIAL killed ca.…”

“…A capillary feeding (CAFE) choice bioassay was used to screen the antifeedant activity of the CDIAL derivatives against adult female Ae. aegypti (LVP strain) 21,57,58 . Briefly, mosquitoes were presented with two capillaries of 10% sucrose as a food source for 18-20 h; the 'control' capillary was treated with 1% DMSO (the carrier solvent for 1 and its derivatives in this assay) while the 'treatment' capillary was treated with 1 or a derivative thereof at a concentration of 1 mM.…”

“…In our efforts to isolate and characterize the bioactive compounds from C. fragrans, we identified cinnamodial (CDIAL, 1), a drimane sesquiterpene with promising toxicity to larval and adult female Ae. aegypti mosquitoes 21 . In addition to exhibiting a similar toxic profile against pyrethroidsusceptible and -resistant strains of Ae.…”

“…In addition to exhibiting a similar toxic profile against pyrethroidsusceptible and -resistant strains of Ae. aegypti, CDIAL was more efficacious than DEET [N,N-Diethyl-meta-toluamide] -the gold standard for insect repellents -at repelling mosquitoes from feeding on blood 21 . Moreover, we demonstrated that the mechanism of the antifeedant activity of CDIAL was through the activation of transient receptor potential A1 (TRPA1) channels 21 .…”