# Discovery of novel benzimidazole resistance mechanisms

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $735,967

## Abstract

Project summary:
Parasitic nematodes impose a massive health and economic burden across much of the developing world,
infecting over one billion people worldwide. The morbidity and mortality inflicted by these devastating
pathogens is partly curtailed by mass drug administration (MDA) programs that depend on the continued
efficacy of a limited portfolio of anthelmintic drugs. Benzimidazole (BZ) compounds are a widely used class of
broad-spectrum anthelmintics that are an indispensable component of this limited chemotherapeutic arsenal.
The prospects of BZ resistance pose a serious threat to the future success of nematode control programs.
These prospects have been realized in the veterinary domain following intensive BZ use and are predicted to
materialize in human medicine with increased selection caused by expanded MDA. Early detection of
resistance-associated alleles in nematode parasite populations is essential to the goal of slowing anthelmintic
resistance and extending the lifespan of this critical drug class. Based on research in the free-living nematode
Caenorhabditis elegans from thirty years ago, parasitic nematode researchers focus on one BZ target, a
nematode-specific beta-tubulin. Despite this knowledge, it is still a complete mystery (1) whether any alleles
cause resistance (i.e. go beyond correlation), (2) the nematode tissues that are sensitive to BZ poisoning,
and (3) the drug-target interactions that cause resistance. In Haemonchus contortus, we have collected both
validated sensitive and resistance samples, and longitudinal samples where resistance has developed over
time. These samples are not available in any human parasitic nematode species. Using quantitative
resistance assays on these resources, we have shown that BZ resistance goes well beyond this single beta-
tubulin target. However, we do not know these independent resistance mechanisms in C. elegans or parasite
species. In Aim 1, we will test explicitly whether alleles correlated with resistance in parasites actually cause
resistance, test the fitness effects of these alleles, identify the tissues targeted by BZ, and characterize the
molecular mechanism for how beta-tubulin in affected by benzimidazoles. In Aim 2, we will discover beta-
tubulin independent mechanisms of resistance using the tractable C. elegans model nematode. In Aim 3, we
will expand our results to H. contortus where genomic and validated strain resources enable discoveries of
conserved resistance mechanisms. It is not possible in any parasitic nematode species to accomplish these
goals. New discoveries are possible only through this interplay between the model nematode C. elegans and
the tractable veterinary parasitic nematode H. contortus. Our results will have direct impacts on how
treatments are administered and resistance is monitored in human parasitic nematodes.

## Key facts

- **NIH application ID:** 10029488
- **Project number:** 1R01AI153088-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Erik Christian Andersen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $735,967
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10029488

## Citation

> US National Institutes of Health, RePORTER application 10029488, Discovery of novel benzimidazole resistance mechanisms (1R01AI153088-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10029488. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*