# Discovery of Hsp100-selective inhibitors for targeting multiple microbial pathogens

> **NIH NIH R01** · KANSAS STATE UNIVERSITY · 2022 · $328,714

## Abstract

PROJECT SUMMARY/ABSTRACT
Pathogenic microorganisms are the cause of diverse infections and diseases worldwide. The emergence of
drug resistant strains increases the infection and mortality rates and demands new approaches and efforts in
the antimicrobial drug discovery. The long-term goal of our research is to understand the role of molecular
chaperones in pathogen growth, survival, and virulence and to apply that knowledge in developing molecular
approaches to combat infectious diseases. The objective of this application is to discover small-molecule
inhibitors of Hsp100 chaperones using high-throughput library screening. The Hsp100 chaperones reactivate
aggregated cellular proteins. A loss of Hsp100 is detrimental for infectivity and survival of a number of bacterial
and protozoan pathogens. Importantly, no apparent Hsp100 orthologs are found in metazoan proteomes. As
the primary target for inhibitor development and testing, we will use the Hsp100 chaperone, ClpB, from
Shigella/Escherichia coli. The following Specific Aims will be pursued: 1. We will perform a sequence of two
screens of a small-molecule library that will interrogate two orthogonal functionalities of ClpB: ATP-dependent
substrate binding and substrate-induced activation of the ATPase activity. 2. We will validate and prioritize
compound hit chemotypes that inhibit ClpB using medicinal chemistry approaches. 3. We will validate the
inhibitory potency of selected hit compounds and test their selectivity towards ClpB in vitro by performing a
number of orthogonal biochemical assays. 4. We will perform preliminary testing of the antimicrobial activity of
the hit compounds in Gram-negative bacteria Escherichia coli, Shigella flexneri, and Shigella sonnei, and
Gram-positive Staphylococcus aureus. The expected outcome of the proposed studies will be the discovery of
validated small-molecule Hsp100-inhibitor candidates for future medicinal chemistry optimization and biological
testing. This approach is innovative because no chaperone-based antimicrobials have been implemented yet.

## Key facts

- **NIH application ID:** 10440373
- **Project number:** 5R01AI141586-04
- **Recipient organization:** KANSAS STATE UNIVERSITY
- **Principal Investigator:** Anuradha Roy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $328,714
- **Award type:** 5
- **Project period:** 2019-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440373

## Citation

> US National Institutes of Health, RePORTER application 10440373, Discovery of Hsp100-selective inhibitors for targeting multiple microbial pathogens (5R01AI141586-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10440373. Licensed CC0.

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