The molecular targets of ivermectin and lotilaner in the human louse Pediculus humanus humanus: New prospects for the treatment of pediculosis

Control of infestation by cosmopolitan lice (Pediculus humanus) is increasingly difficult due to the transmission of parasites resistant to pediculicides. However, since the targets for pediculicides have no been identified in human lice so far, their mechanisms of action remain largely unknown. The macrocyclic lactone ivermectin is active against a broad range of insects including human lice. Isoxazolines are a new chemical class exhibiting a strong insecticidal potential. They preferentially act on the γ-aminobutyric acid (GABA) receptor made of the resistant to dieldrin (RDL) subunit and, to a lesser extent on glutamate-gated chloride channels (GluCls) in some species. Here, we addressed the pediculicidal potential of isoxazolines and deciphered the molecular targets of ivermectin and the ectoparasiticide lotilaner in the human body louse species Pediculus humanus humanus. Using toxicity bioassays, we showed that fipronil, ivermectin and lotilaner are efficient pediculicides on adult lice. The RDL (Phh-RDL) and GluCl (Phh-GluCl) subunits 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 16.0 μM and 9.3 μM. 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 of 40.7 nM, whereas it had no effect on Phh-GluCl. We report here for the first time the insecticidal activity of isoxazolines on human ectoparasites and reveal the mode of action of ivermectin and lotilaner on GluCl and RDL channels from human lice. These results emphasize an expected extension of the use of the isoxazoline drug class as new pediculicidal agents to tackle resistant-louse infestations in humans.

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Distinct molecular targets for macrocyclic lactone and isoxazoline insecticides in the human louse: new prospects for the treatment of pediculosis

10.1101/2020.08.06.239400 ◽

2020 ◽

Author(s):

Nicolas Lamassiaude ◽

Berthine Toubate ◽

Cédric Neveu ◽

Pierre Charnet ◽

Catherine Dupuy ◽

...

Keyword(s):

Mode Of Action ◽

Chloride Channels ◽

Macrocyclic Lactone ◽

Control Strategies ◽

Molecular Targets ◽

Drug Repurposing ◽

Health Concern ◽

The Novel ◽

Pediculus Humanus ◽

Significant Public Health

AbstractBackgroundControl 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 γ-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 findingsUsing 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 µM and 9.3 µM. 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 µM, whereas it had no effect on Phh-GluCl.ConclusionsWe 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.Autorship summaryWhy was this study done?Human cosmopolitan lice are responsible for pediculosis, which represent a significant public health concern. Resistant lice against insecticides and lack of safety of the treatments for human and environment is a growing issue worldwide. Here we investigated the efficacy on lice of the classical macrocyclic lactone drug, ivermectin, and the novel isoxazoline drug, lotilaner. This study was done to decipher their mode of action at the molecular and funtional levels in order to propose new strategies to control lice infestation.What did the researchers do and find?Our bioassay results indicate that ivermectin and lotilaner were potent at killing human adult lice, with lotilaner showing a higher efficacy than ivermectin. Furthermore, we identified and pharmacologically characterized the first glutamate- and GABA-gated chloride channels ever described in human lice yet. Mechanistically, our molecular biology and electrophysiology findings demonstrate that ivermectin acted preferentially at glutamate channels while lotilaner specifically targeted GABA channels.What do these findings mean?These results provide new insights in the understanding of the insecticide mode of action and highlight the isoxazolines as a new drug-repurposing opportunity for pest control strategies.

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