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Infections from parasitic nematodes (or roundworms) contribute to a significant disease burden and productivity losses for humans and livestock. The limited number of anthelmintics (or antinematode drugs) available today to treat these infections are rapidly losing their efficacy as multidrug resistance in parasites becomes a global health challenge. We propose an engineering approach to discover an anthelmintic drug combination that is more potent at killing wild-type Caenorhabditis elegans worms than four individual drugs. In the experiment, freely swimming single worms are enclosed in microfluidic drug environments to assess the centroid velocity and track curvature of worm movements. After analyzing the behavioral data in every iteration, the feedback system control (FSC) scheme is used to predict new drug combinations to test. Through a differential evolutionary search, the winning drug combination is reached that produces minimal centroid velocity and high track curvature, while requiring each drug in less than their EC 50 concentrations. The FSC approach is model-less and does not need any information on the drug pharmacology, signaling pathways, or animal biology. Toward combating multidrug resistance, the method presented here is applicable to the discovery of new potent combinations of available anthelmintics on C. elegans , parasitic nematodes, and other small model organisms.
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Microfluidic bioassay to characterize parasitic nematode phenotype and anthelmintic resistance
SUMMARY With increasing resistance to anti-parasitic drugs, it has become more important to detect and recognize phenotypes of resistant isolates. Molecular methods of detecting resistant isolates are limited at present. Here, we introduce a microfluidic bioassay to measure phenotype using parameters of nematode locomotion. We illustrate the technique on larvae of an animal parasite Oesophagostomum dentatum. Parameters of sinusoidal motion such as propagation velocity, wavelength, wave amplitude, and oscillation frequency depended on the levamisole-sensitivity of the isolate of parasitic nematode. The levamisole-sensitive isolate (SENS) had a mean wave amplitude of 135 μ m, which was larger than 123 μ m of the levamisole-resistant isolate (LEVR). SENS had a mean wavelength of 373 μ m, which was less than 393 μ m of LEVR. The mean propagation velocity of SENS, 149 μ m s −1 , was similar to LEVR, 143 μ m s −1 . The propagation velocity of the isolates was inhibited by levamisole in a concentration-dependent manner above 0·5 μ m . The EC 50 for SENS was 3 μ m and the EC 50 for LEVR was 10 μ m . This microfluidic technology advances present-day nematode migration assays and provides a better quantification and increased drug sensitivity. It is anticipated that the bioassay will facilitate study of resistance to other anthelmintic drugs that affect locomotion.
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- Award ID(s):
- 1000808
- PAR ID:
- 10334511
- Date Published:
- Journal Name:
- Parasitology
- Volume:
- 138
- Issue:
- 1
- ISSN:
- 0031-1820
- Page Range / eLocation ID:
- 80 to 88
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1017/S0031182010001010
