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Identifying inhibitors of the bacterial peptidyl-tRNA hydrolase

Award Number: R21AI196497
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/03/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Identifying inhibitors of the bacterial peptidyl-tRNA hydrolase - Peptidyl-tRNA hydrolase (Pth) is an essential bacterial enzyme critical for protein synthesis and whose inactivation leads to cell death. Pth recycles peptidyl-tRNAs that prematurely dissociate from the translated ribosome. Additionally, Pth is involved in rescuing the large ribosomal subunit that remains associated with peptidyl-tRNA after the splitting of the stalled ribosome. It may also contribute to other ribosome rescue mechanisms. Despite its essentiality, efforts to identify Pth inhibitors have been hindered by challenges in generating suitable substrates for high-throughput screening (HTS). To address this, we designed an oligonucleotide-based Pth substrate that mimics peptidyl-tRNA and used it to develop and validate an HTS assay based on the Förster resonance energy transfer (FRET). Limited preliminary studies have identified several compounds with inhibitory activity against Pth from Escherichia coli and Klebsiella pneumoniae. This proposal aims to advance Pth inhibitor development by synthesizing and optimizing derivatives of the most potent hits with sub-micromolar IC50 values to enhance their activity against K. pneumoniae Pth and improve cellular uptake. Concurrently, we will expand the screening campaign to identify novel inhibitor scaffolds. The interaction of these compounds with Pth will be studied by SPR and X-ray crystallography, to guide medicinal chemistry optimization. In addition, we will characterize their mechanisms of action, cellular targets, effects on protein synthesis, and potential resistance mechanisms. The anticipated outcome is the identification of a lead inhibitor scaffold suitable for preclinical development as a foundation for a novel antibiotic platform.


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 = $440,908 )
2026	2026	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Allergy and Infectious Diseases Research	000	1	2/3/2026	NEW	$440,908
														Subtotal = $440,908

Grand Total All Awards = $440,908

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Identifying inhibitors of the bacterial peptidyl-tRNA hydrolase

Award Number: R21AI196497

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/03/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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