Structural model, functional modulation by ivermectin and tissue localization of Haemonchus contortus P-glycoprotein-13

Marion David (1) , Chantal Lebrun (2) , Thomas Duguet (3) , Franck Talmont , Robin Beech (4) , Stéphane Orlowski (5, 6, 7) , François André (5, 5, 8, 6) , Roger K. Prichard (9) , Anne Lespine (2)

1 Vect-Horus
2 ToxAlim - ToxAlim
3 CIRIMAT - Centre interuniversitaire de recherche et d'ingenierie des matériaux
4 Institute of Parasitology
5 I2BC - Institut de Biologie Intégrative de la Cellule
6 B3S - Département Biochimie, Biophysique et Biologie Structurale
7 LPSM - Laboratoire des Protéines et Systèmes Membranaires
8 LSOD - Stress Oxydants et Détoxication
9 Institute of Parasitology

Haemonchus contortus, one of the most economically important parasites of small ruminants, has become resistant to the anthelmintic ivermectin. Deciphering the role of P-glycoproteins in ivermectin resistance is desirable for understanding and overcoming this resistance. In the model nematode, Caenorhabditis elegans, P-glycoprotein-13 is expressed in the amphids, important neuronal structures for ivermectin activity. We have focused on its ortholog in the parasite, Hco-Pgp-13. A 3D model of Hco-Pgp-13, presenting an open inward-facing conformation, has been constructed by homology with the Cel-Pgp-1 crystal structure. In silico docking calculations predicted high affinity binding of ivermectin and actinomycin D to the inner chamber of the protein. Following in vitro expression, we showed that ivermectin and actinomycin D modulated Hco-Pgp-13 ATPase activity with high affinity. Finally, we found in vivo Hco-Pgp-13 localization in epithelial, pharyngeal and neuronal tissues. Taken together, these data suggest a role for Hco-Pgp-13 in ivermectin transport, which could contribute to anthelmintic resistance.

Mots clés: ABC transporters; Haemonchus contortus; Homology modeling; Ivermectin; Nematode; P-glycoprotein

Domaines: Sciences du Vivant [q-bio]

Marion David, Chantal Lebrun, Thomas Duguet, Franck Talmont, Robin Beech, et al.. Structural model, functional modulation by ivermectin and tissue localization of Haemonchus contortus P-glycoprotein-13. International journal for parasitology. Drugs and drug resistance, 2018, 8 (1), pp.145--157. ⟨10.1016/j.ijpddr.2018.02.001⟩. ⟨hal-02177610⟩