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Pharyngeal Pumping and Tissue-Specific Transgenic P-Glycoprotein Expression Influence Macrocyclic Lactone Susceptibility in Caenorhabditis elegans
- Source :
- Pharmaceuticals, Pharmaceuticals, MDPI, 2021, 14 (2), pp.1-17. ⟨10.3390/ph14020153⟩, Pharmaceuticals, Vol 14, Iss 153, p 153 (2021), Volume 14, Issue 2
- Publication Year :
- 2021
- Publisher :
- HAL CCSD, 2021.
-
Abstract
- Macrocyclic lactones (MLs) are widely used drugs to treat and prevent parasitic nematode infections. In many nematode species including a major pathogen of foals, Parascaris univalens, resistance against MLs is widespread, but the underlying resistance mechanisms and ML penetration routes into nematodes remain unknown. Here, we examined how the P-glycoprotein efflux pumps, candidate genes for ML resistance, can modulate drug susceptibility and investigated the role of active drug ingestion for ML susceptibility in the model nematode Caenorhabditis elegans. Wildtype or transgenic worms, modified to overexpress P. univalens PGP-9 (Pun-PGP-9) at the intestine or epidermis, were incubated with ivermectin or moxidectin in the presence (bacteria or serotonin) or absence (no specific stimulus) of pharyngeal pumping (PP). Active drug ingestion by PP was identified as an important factor for ivermectin susceptibility, while moxidectin susceptibility was only moderately affected. Intestinal Pun-PGP-9 expression elicited a protective effect against ivermectin and moxidectin only in the presence of PP stimulation. Conversely, epidermal Pun-PGP-9 expression protected against moxidectin regardless of PP and against ivermectin only in the absence of active drug ingestion. Our results demonstrate the role of active drug ingestion by nematodes for susceptibility and provide functional evidence for the contribution of P-glycoproteins to ML resistance in a tissue-specific manner.
- Subjects :
- Macrocyclic lactones
600 Technik, Medizin, angewandte Wissenschaften::630 Landwirtschaft::630 Landwirtschaft und verwandte Bereiche
[SDV]Life Sciences [q-bio]
lcsh:R
lcsh:Medicine
lcsh:RS1-441
P-glycoprotein
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::616 Krankheiten
Caenorhabditis elegans
Article
lcsh:Pharmacy and materia medica
Drug resistance
parasitic diseases
Parasitology
[SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::615 Pharmakologie, Therapeutik
Nematode
Subjects
Details
- Language :
- English
- ISSN :
- 14248247
- Database :
- OpenAIRE
- Journal :
- Pharmaceuticals, Pharmaceuticals, MDPI, 2021, 14 (2), pp.1-17. ⟨10.3390/ph14020153⟩, Pharmaceuticals, Vol 14, Iss 153, p 153 (2021), Volume 14, Issue 2
- Accession number :
- edsair.doi.dedup.....9489f4a1605b402a69621e116223218f