Ascariasis and hookworm infections are carried by 1.6 billion people throughout the world and in 2 percent of cases cause loss of life. Anthelmintics, including levamisole and related drugs (pyrantel and oxantel), are used to combat nematode parasites, but the development of resistance is a concern. The long-range objective is to improve and protect human health by protecting the efficacy of anthelmintic drugs by controlling and reversing resistance. The objective of the application is to identify mechanisms that regulate the sensitivity of the response of nematode parasite levamisole receptor channels. Our central hypothesis is that competing processes (phosphorylation-dephosphorylation) modulate levamisole responses, and that modification of the processes can produce a decrease or increase in resistance. We developed this hypothesis on the basis of: 1) analysis showing consensus regulatory phosphorylation sites on levamisole receptors; 2) our published and preliminary data showing reduced patency of levamisole receptor channels in resistant nematodes; 3) strong preliminary data that shows levamisole responses are reduced by inhibition of protein kinases. The rationale for the research is that, once mechanisms for regulating levamisole receptor channels are known, pharmacological approaches can be formulated to prevent or overcome resistance, and to maintain the efficacy of levamisole and related anthelmintics. In most experiments we will use electrophysiological techniques on Ascaris suum to examine the properties of the receptor channel. Muscle-flap preparations with current- and voltage-clamp techniques will be used for screening drug effects. We will use muscle-vesicle preparations and patch-clamp technology to measure effects on gating kinetics of levamisole receptor channels of nematode parasites. We will pursue two specific aims to accomplish our current objective: 1) determine mechanisms by which nematode parasites limit their response (P-open) of receptors, and become resistant to levamisole; 2) determine mechanisms that increase P-open values of receptors, in order to reverse resistance to levamisole. We will test our hypothesis that levamisole resistance can be reversed by increased receptor phosphorylation in different species of resistant nematodes. The research is innovative because few groups carry out parasite electrophysiology and others have not developed nematode parasite muscle-vesicle preparations for patch-clamp recordings from levamisole receptor channels. We expect the research to identify mechanisms that decrease levamisole responses (reduce P-open) so parasites become resistant to levamisole and to demonstrate how this resistance can be reversed. The research is significant because application of the results is expected to lead towards methods that will control and overcome resistance to anthelmintics of the levamisole class.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047194-04
Application #
6699929
Study Section
Special Emphasis Panel (ZRG1-TMP (03))
Program Officer
Coyne, Philip Edward
Project Start
2001-01-01
Project End
2005-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
4
Fiscal Year
2004
Total Cost
$216,750
Indirect Cost
Name
Iowa State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
005309844
City
Ames
State
IA
Country
United States
Zip Code
50011
Martin, Richard John (2018) Nuclear option prevents hyperinfection in the Strongyloides worm war. Proc Natl Acad Sci U S A 115:9-11
Abongwa, Melanie; Marjanovic, Djordje S; Tipton, James G et al. (2018) Monepantel is a non-competitive antagonist of nicotinic acetylcholine receptors from Ascaris suum and Oesophagostomum dentatum. Int J Parasitol Drugs Drug Resist 8:36-42
Verma, Saurabh; Kashyap, Sudhanva Srinivas; Robertson, Alan Patrick et al. (2017) Functional genomics in Brugia malayi reveal diverse muscle nAChRs and differences between cholinergic anthelmintics. Proc Natl Acad Sci U S A 114:5539-5544
Zheng, Fudan; Du, Xiangwei; Chou, Tsung-Han et al. (2017) (S)-5-ethynyl-anabasine, a novel compound, is a more potent agonist than other nicotine alkaloids on the nematode Asu-ACR-16 receptor. Int J Parasitol Drugs Drug Resist 7:12-22
Abongwa, Melanie; Martin, Richard J; Robertson, Alan P (2017) A BRIEF REVIEW ON THE MODE OF ACTION OF ANTINEMATODAL DRUGS. Acta Vet (Beogr) 67:137-152
Zheng, Fudan; Robertson, Alan P; Abongwa, Melanie et al. (2016) The Ascaris suum nicotinic receptor, ACR-16, as a drug target: Four novel negative allosteric modulators from virtual screening. Int J Parasitol Drugs Drug Resist 6:60-73
Abongwa, Melanie; Buxton, Samuel K; Robertson, Alan P et al. (2016) Curiouser and Curiouser: The Macrocyclic Lactone, Abamectin, Is also a Potent Inhibitor of Pyrantel/Tribendimidine Nicotinic Acetylcholine Receptors of Gastro-Intestinal Worms. PLoS One 11:e0146854
Abongwa, Melanie; Baber, Katherine E; Martin, Richard J et al. (2016) The cholinomimetic morantel as an open channel blocker of the Ascaris suum ACR-16 nAChR. Invert Neurosci 16:10
Abongwa, Melanie; Buxton, Samuel K; Courtot, Elise et al. (2016) Pharmacological profile of Ascaris suum ACR-16, a new homomeric nicotinic acetylcholine receptor widely distributed in Ascaris tissues. Br J Pharmacol 173:2463-77
Martin, R J; Puttachary, S; Buxton, S K et al. (2015) The Conqueror Worm: recent advances with cholinergic anthelmintics and techniques excite research for better therapeutic drugs. J Helminthol 89:387-97

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