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Hit-to-lead development of imidazopyridine containing compounds as treatment for babesiosis

Award Number: K08AI198935
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 06/15/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Hit-to-lead development of imidazopyridine containing compounds as treatment for babesiosis - PROJECT SUMMARY/ABSTRACT Babesiosis, the illness caused by the tickborne malaria-like parasite Babesia, is an emerging infectious disease for which existing antimicrobials are inadequate in immunocompromised hosts. There is a critical need for development of new therapeutics. A series of 28 imidazopyridine-containing compounds (ICCs) which have been identified as highly potent in vitro growth inhibitors of Babesia duncani can potentially fill this need. EC50s of these small molecules are as low as 10 nM and murine pharmacokinetic data- available for most of these compounds- show therapeutic blood levels for treatment of babesiosis are achievable. In prior study of organisms including Cryptosporidium and Trypanosoma ICCs are shown to act on methionyl tRNA synthetase (MetRS). The goal of this project is to further develop these novel antimicrobials through hit-to-lead studies including Specific Aim 1) target identification, Specific Aim 2) identification of drug resistance potential, and Specific Aim 3) proof of efficacy in a mouse model of disease. More conclusive evidence that ICCs target the Babesia MetRS will be generated by expressing recombinant Babesia duncani MetRS, with enzyme inhibition and binding by ICCs measured using ATP:PPI assay (SA1). Prior use of an ICC, UW-2093, in a calf model of cryptosporidiosis revealed that single amino acid mutations to MetRS could lead to drug resistance. In light of homology between Babesia and Cryptosporidium MetRS active site amino acid sequences a similar single amino acid mutation is predicted to reduce susceptibility of Babesia to UW-2093. A CRISPR/Cas9 system will be used to generate Babesia divergens with modified MetRS. This study will be complemented by in vitro spontaneous selection of resistance mutations under UW-2093 drug pressure with whole genome sequencing used to identify SNPs (SA2A). Comparison will be drawn between spontaneous selection under pressure of UW-2093 alone v. UW-2093 + atovaquone with the hypothesis that dual therapy will prevent selection of resistant parasites (SA2B). Murine studies will include pilot efficacy study of high dose ICC treatment in a mouse model of Babesiosis, followed by dose down study of the most promising lead compound in effort to determine the 90% effective dose (SA3). This project will address the need for improved babesiosis treatments by identifying a new drug target, developing a new set of lead compounds, and identifying modes of resistance and strategies to mitigate them. The work outlined above will, in tandem with formal coursework in protein expression and analysis, molecular biology, biostatistics, and bioinformatics, serve as an ideal training platform to catalyze the growth of the early-stage investigator, into an independent researcher. The primary investigator has assembled a strong mentorship and scientific advisor team that provides expertise in drug discovery, pharmacology, and molecular parasitology as well as a rich experience training early career scientists.


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 = $176,094 )
2026	2026	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	1	6/16/2026	NEW	$176,094
														Subtotal = $176,094

Grand Total All Awards = $176,094

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Hit-to-lead development of imidazopyridine containing compounds as treatment for babesiosis

Award Number: K08AI198935

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 06/15/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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