# Identifying GroEL inhibitors with activity against replicating and non-replicating Mycobacterium tuberculosis

> **NIH NIH R03** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $83,150

## Abstract

PROJECT SUMMARY
 Current treatments for Mycobacterium tuberculosis infections suffer from complicated regimens leading
to patient non-compliance, increasing incidences of antibiotic-resistant strains, and inefficacy against non-
replicating bacteria in granulomas that cause latent stages of disease. The urgency to develop new
tuberculosis therapeutics is highlighted by the fact that ~25% of people globally are infected with asymptomatic
latent disease, and over 10 million cases of active tuberculosis infection are reported annually, with 1.6 million
deaths attributed to the disease. To address this dilemma, our strategy is to develop new antibiotic classes that
exploit unique biological targets, specifically bacterial GroEL/ES chaperonin systems. The primary function of
GroEL/ES chaperonin systems are to fold newly translated proteins into their functional conformations. M.
tuberculosis has two GroEL homologs: GroEL1 is not essential but is important for cytokine-dependent
granuloma formation where non-replicating bacteria contribute to latent disease, while GroEL2 is essential and
likely functions as the canonical housekeeping chaperonin for folding proteins. Thus, our central hypothesis is
that inhibitors that can target the two GroEL homologs in M. tuberculosis will be effective against both actively-
replicating bacteria and preventing bacteria from forming and residing in granulomas in a non-replicating state.
Supporting this hypothesis, our recent studies have indicated that bioactive molecules, in particular those with
antibiotic properties, may have a significant predisposition for inhibiting GroEL/ES chaperonin systems.
Furthermore, we also identified GroEL/ES inhibitors that exhibited moderate antibiotic effects against actively
replicating M. tuberculosis, and conversely found that bedaquiline and delamanid were weak GroEL/ES
inhibitors. Towards our long-term goal of developing such mechanistically unique antibiotic candidates, our
objective in the proposed study is to identify new hit-to-lead antibiotic candidates that are more potent at
inhibiting GroEL/ES chaperonin systems and killing actively replicating and non-replicating M. tuberculosis. We
will take a two-pronged approach to accomplish this objective. In Aim 1, we will screen our larger library of
known GroEL/ES inhibitors to identify new scaffolds with greater potency against actively-replicating and non-
replicating M. tuberculosis. In Aim 2, we will screen a library of known M. tuberculosis inhibitors to identify hits
that can target GroEL/ES chaperonin systems. The proposed study will have significant impact for developing
new therapeutic candidates with efficacy against all stages of tuberculosis, which would be a significant
advance to augment current therapeutics that primarily target actively-replicating bacteria.

## Key facts

- **NIH application ID:** 10125105
- **Project number:** 5R03AI151532-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Steven Michael Johnson
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $83,150
- **Award type:** 5
- **Project period:** 2020-03-10 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125105

## Citation

> US National Institutes of Health, RePORTER application 10125105, Identifying GroEL inhibitors with activity against replicating and non-replicating Mycobacterium tuberculosis (5R03AI151532-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10125105. Licensed CC0.

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