Ascariasis and hookworm infection affect 1.6 billion people across the world. Anthelmintics, including levamisole and related drugs (pyrantel), are used to combat nematode parasites, and resistance is a threat. Our long-range objective is to improve human health by increasing the efficacy of anthelmintic drugs by identifying approaches to reverse resistance. The objective of this application is to test single-channel properties of levamisole receptors and a model that describes changes in the sensitivity of nematodes to levamisole and alters potency. Our central hypothesis is that the structure and pore of the L-subtype acetylcholine receptor ion-channel on nematode muscle makes it more sensitive to levamisole and more permeable to Ca;and the increased response of acetylcholine channels (modulation) produced by the neuropeptide, AF2,involves cAMP, Ca entry and kinase activity. The rationale for the research is that, as the mechanisms for modulating responses to levamisole activated receptor channels become known, pharmacological approaches can be formulated to overcome resistance. We will use muscle preparations of A. suum, C. elegans and null-mutants with current-clamp, voltage-clamp and patch-clamp technology to test the Ca permeability and subunit composition of L-subtype acetylcholine channels and to test a model for AF2 modulation. We will pursue 3 aims: 1) determine the Ca permeability of N-, L- and B- subtypes of A. suum muscle acetylcholine receptors and thereby identify a preferred target site;2) determine in patch-clamp experiments in C. elegans, the subunit requirements of the L-subtype acetylcholine channel;3) characterize, n A. suum muscle, the mechanism &pharmacology by which calcium and AF2 affect the opening of different AChR channel subtypes, in order to increase responses and potency of cholinergic anthelmintics. The research is innovative because we are combining new knowledge from C. elegans with advanced electrophysiology of nematode parasites including muscle-vesicle preparations for patch-clamp recordings. We expect the research to identify additional strategies that increase the potency of cholinergic anthelmintics. The research is significant because application of the results will to lead to new approaches to control and overcome resistance to anthelmintics of the levamisole class.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-DDR-N (01))
Program Officer
Rogers, Martin J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Iowa State University
Veterinary Sciences
Schools of Veterinary Medicine
United States
Zip Code
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
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
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
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
Robertson, Alan P; Puttachary, Sreekanth; Buxton, Samuel K et al. (2015) Tribendimidine: mode of action and nAChR subtype selectivity in Ascaris and Oesophagostomum. PLoS Negl Trop Dis 9:e0003495

Showing the most recent 10 out of 49 publications