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Uncovering Resistance Mechanisms of the Anthelmintic Drugs Levamisole and Pyrantel

Award Number: K99AI199993
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/04/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Uncovering Resistance Mechanisms of the Anthelmintic Drugs Levamisole and Pyrantel - Project summary/abstract Parasitic nematodes are responsible for a myriad of neglected tropical diseases that lead to serious health burdens and create significant socio-economic challenges. Nicotinic acetylcholine receptor (nAChR) agonists, such as levamisole and pyrantel, are a critical class of anthelmintic drugs used to combat parasitic nematode infections in humans, livestock, and domestic animals worldwide. Unfortunately, resistance to nAChR agonists is prevalent across cattle, equine, and ruminant parasites and is an emerging issue in human hookworm and filarial parasite populations. Consequently, we urgently need to identify the mechanisms of resistance (MoR) to nAChR agonists to improve treatment strategies and slow resistance. To identify how nematodes have evolved resistance to nAChR agonists, it is imperative to investigate the role that target site resistance (TSR) and non-target site resistance (NTSR) mechanisms play in anthelmintic resistance. Because both TSR and NTSR mechanisms likely contribute to resistance against nAChR agonists, I propose to investigate how multiple traits influence the MoR to levamisole and pyrantel. I will examine how nAChR agonists affect nematode development, gene transcription, and metabolite abundances to comprehensively define levamisole and pyrantel resistance. Importantly, disentangling the role of genes in complex traits in parasitic nematodes is impossible. Therefore, I will use the tractability of Caenorhabditis elegans to answer these critical questions about anthelmintic MoR. Preliminary data from a genome-wide association study (GWAS) has shown that additional genes, beyond those implicated in the literature, are involved in levamisole and pyrantel resistance across C. elegans natural populations. In Aim 1, I will narrow quantitative trait loci (QTL) from the GWAS associated with variation in levamisole and pyrantel resistance. Second, I will collect gene transcription and metabolite abundance data on C. elegans strains sensitive and resistant to nAChR agonists that will allow me to better understand the complex interactions and identify candidate genes that contribute to the MoR of nAChR agonists. In Aim 2, I will use CRISPR-Cas9 genome editing, established high-throughput assays (HTA), and competition assays to test the effects of genetic variants in each strain and identify nAChR agonist resistance genes. Finally, conserved molecular determinants of pyrantel response identified using C. elegans likely underlie common MoR in closely related parasitic nematodes. Therefore, in Aim 3, I will identify connections between the C. elegans molecular determinants identified for pyrantel resistance and nAChR agonist resistance markers in Anylostoma caninum canine hookworm samples. I will use egg hatch assays, larval development assays, and amplicon sequencing to identify and validate variants associated with pyrantel resistance in A. caninum. Identifying conserved molecular mechanisms of resistance from C. elegans to parasites is imperative to inform strategies to combat anthelmintic resistance.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $125,000 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	1	8/4/2026	NEW	$125,000
														Subtotal = $125,000

Grand Total All Awards = $125,000

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Uncovering Resistance Mechanisms of the Anthelmintic Drugs Levamisole and Pyrantel

Award Number: K99AI199993

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/04/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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