The role of amphidial drug uptake in the mode of action and resistance to ivermectin in nematodes of livestock

Información del proyecto

IDRAM

Identificador del acuerdo de subvención: 747676

DOI

10.3030/747676

Proyecto finalizado el 3 Mayo 2017

Fecha de la firma de la CE 23 Marzo 2017

Fecha de inicio 1 Septiembre 2017

Fecha de finalización 31 Agosto 2019

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 195 454,80

Aportación de la UE

€ 195 454,80

Coordinado por

UNIVERSITY OF GLASGOW
United Kingdom

Objetivo

The macrocyclic lactones such as ivermectin are the cornerstone for the treatment of key nematode infections of livestock, crops and man. Resistance to many of these broad-spectrum anthelmintics is becoming commonplace, while new classes of active compounds are increasingly difficult to find, threatening food supplies and public heatlh worldwide. The exact molecular and biochemical mechanisms of resistance, particularly to the widely used macrocyclic lactone class, are still poorly understood, impeding the development of efficient strategies to control drug resistance. I hypothesize that the amphidial sensory organs of nematodes are the major route of macrocyclic lactone drug uptake and that mutations in this uptake mechanism represents the primary source of drug resistance. In the first phase of the project, I will develop laboratory methods for testing amphid function in two parasitic nematodes of veterinary significance, the trichostrongyles Haemonchus contortus and Teladorsagia circumcincta. These techniques will be applied on drug resistant and sensitive isolates to evaluate the role of amphids in ivermectin uptake. In the second phase, I will use the C. elegans model to generate mutants resistant to three major classes of anthelmintic drugs, ivermectin, the benzimidazole albendazole and the imidazothiazole levamisole. I will then apply genomic tools to identify alleles responsible of this multi-drug resistance phenotype. This project aims to understand the link between amphid defects, anthelmintic drug uptake, and development of resistance, and will generate a thorough knowledge of this unexplored and apparently widespread resistance mechanism in nematodes. These results will also pave the way to the implementation of a fast and reliable measurement of drug resistance in the field. On the whole, the project will bring a direct contribution to current veterinary and public health challenges by suggesting new strategies to limit the emergence of drug resistance.

Ámbito científico (EuroSciVoc)

• ciencias médicas y de la salud › ciencias de la salud › salud pública y medio ambiental
• ciencias naturales › ciencias biológicas › genética › mutación
• ciencias agrícolas › agricultura, silvicultura y pesca › agricultura
• ciencias agrícolas › ciencias animales y lácteas › mascotas › ganadería
• ciencias médicas y de la salud › medicina básica › farmacología y farmacia › farmacorresistencia › resistencia a múltiple fármacos

Palabras clave

• anthelmintic resistance
• ivermectin
• nematodes
• drug uptake
• amphids
• macrocyclic lactones
• mulit-drug resistance
• trichostrongyle nematodes

Programa(s)

• H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions PROGRAMA PRINCIPAL
  
• H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
  

Tema(s)

• MSCA-IF-2016 - Individual Fellowships
  

Régimen de financiación

MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

Convocatoria de propuestas

H2020-MSCA-IF-2016

Coordinador

UNIVERSITY OF GLASGOW

• Aportación neta de la UEn: € 195 454,80
• Dirección: UNIVERSITY AVENUE ; G12 8QQ Glasgow ; Reino Unido
• Región: Scotland › West Central Scotland › Glasgow City
• Tipo de actividad: Higher or Secondary Education Establishments
• Coste total: € 195 454,80