Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.06.239400v1?rss=1 Authors: Charvet, C. L., Lamassiaude, N., Toubate, B., Neveu, C., Charnet, P., Dupuy, C., Debierre-Grockiego, F., Dimier-Poisson, I. Abstract: Background Control of infestation by cosmopolitan lice (Pediculus humanus) is increasingly difficult due to the transmission of resistant parasites to pediculicides. However, since the targets for pediculicides have no been identified in human lice so far, their mechanism of action remain largely unknown. The macrocyclic lactone, ivermectin is active against a broad range of insects including human lice. Isoxazolines are a recent new chemical class targeting the {gamma}-aminobutyric acid (GABA) receptor made of the resistant to dieldrin (RDL) subunit and exhibiting a strong insecticidal potential. Here, we addressed the pediculicidal potential of isoxazolines and deciphered the molecular targets of ivermectin and the novel ectoparasiticide lotilaner in the human body louse species Pediculus humanus humanus. Methods and findings Using toxicity bioassays, we showed that fipronil, ivermectin and lotilaner are efficient pediculicides on adult lice. The RDL (Phh-RDL) and glutamate-gated chloride channel subunits (Phh-GluCl) were cloned and characterized by two-electrode voltage clamp electrophysiology in Xenopus laevis oocytes. Phh-RDL and Phh-GluCl formed functional homomeric receptors respectively gated by GABA and L-glutamate with EC50 values of 6.4 {micro}M and 9.3 {micro}M. Importantly, ivermectin displayed a super agonist action on Phh-Glucl whereas Phh-RDL receptors were weakly affected. Reversally, lotilaner strongly inhibited the GABA-evoked currents in Phh-RDL with an IC50 value 0.5 {micro}M, whereas it had no effect on Phh-GluCl. Conclusions We report here for the first time the pediculicidal potential of isoxazolines and reveal the distinct mode of action of ivermectin and lotilaner on GluCl and RDL channels from human lice. These results emphasize the clear repurposing future of the isoxazoline drug class to provide new pediculicidal agents to tackle resistant-louse infestations in humans. Copy rights belong to original authors. Visit the link for more info