# Selective modulation of bacterial chaperonins by targeting novel small molecule binding sites

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $434,059

## Abstract

PROJECT SUMMARY: The growing incidences of antibiotic resistance is epitomized by the emergence of six
multi-drug resistant bacteria referred to as the “ESKAPE” pathogens: Enterococcus faecium, Staphylococcus
aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter
species. Without research to develop new antibiotics that are effective against these drug resistant pathogens,
we risk regressing to a pre-antibiotic era where infections were a leading cause of morbidity and mortality. To
counter this threat, the long-term goal of this research is to develop new antibiotics that function by targeting
bacterial GroEL chaperonin systems. GroEL is a centralized molecular machine that maintains the proper
structure and function of hundreds of other proteins. Thus, targeting this one molecular machine will have the
cascading effect of inhibiting hundreds of proteins at once, the functional losses of which bacteria will not be
able to recover from. A caveat to this strategy is that human cells have a mitochondrial counterpart, called
HSP60, and there remains the possibility of inhibitor cross-talk that could lead to toxic effects on host tissues.
The central hypothesis is that the structural and functional divergence between bacterial and mammalian
chaperonins, as well as other mammalian proteins, will allow the selective targeting of small molecule inhibitors
for GroEL and bacteria without toxic side effects to human cells. This hypothesis has been formulated on the
basis of well-established findings on chaperonin structure and function presented in the literature, and
preliminary data for chaperonin inhibitors produced in the applicants' laboratories. In particular, human HSP60
functions as a single-ring oligomer, which removes many of the allosteric transitions that regulate the function
of double-ring bacterial GroEL. In addition, preliminary data suggest there are multiple distinct binding sites on
bacterial GroEL that compounds can interact with to block chaperonin function. Thus, the possibility of small
molecules targeting these unique binding sites to selectively inhibit bacterial GroEL over HSP60 and other
human proteins is high. The overall objective of this proposal is to identify these unique allosteric binding sites,
elucidate the structural/functional mechanisms of action for molecules binding to these sites, and define the
selectivity profiles for site-specific inhibitors in vitro and in cells. The rationale for the proposed studies is that
delineating the precise structural/functional mechanisms of action of chaperonin inhibitors will permit the
rational development GroEL-targeting antibiotic candidates. The approach is innovative because it proposes a
unique and unexplored strategy of exploiting proteostasis machinery – specifically GroEL chaperonins – for killing
infectious bacteria. Without a fundamental shift in strategy for treating infectious diseases, antibiotic resistance
will continue to ris...

## Key facts

- **NIH application ID:** 9889963
- **Project number:** 5R01GM120350-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Steven Michael Johnson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $434,059
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9889963

## Citation

> US National Institutes of Health, RePORTER application 9889963, Selective modulation of bacterial chaperonins by targeting novel small molecule binding sites (5R01GM120350-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9889963. Licensed CC0.

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