# Inhibition of the Bacterial LexA Repressor-Protease to Halt SOS Response-Mediated Resistance and Biofilm Formation

> **NIH NIH F31** · EMORY UNIVERSITY · 2020 · $45,520

## Abstract

Project Summary/Abstract
 The overuse and misuse of antibiotics has put evolutionary pressure on bacteria to alter
or bypass the targets of drugs or otherwise develop resistance, rendering a large percentage of
our available medicines and pesticides ineffective. Novel antibiotics have afforded temporary
relief due to quick development of resistance, although several pharmaceutical companies have
withdrawn from this area of research. Bacterial biofilms further complicate treatment of many
bacterial infections. These cell conglomerates contribute to a variety of health conditions and are
known to colonize the surfaces of most medical devices. Moreover, they shelter high numbers of
persister cells— “dormant” cells which are non-growing and tolerant of most antibiotics.
Unfortunately, most existing therapies target metabolic processes which are suspended in these
transient subpopulations of bacteria. Altogether we are facing a perfect storm of resistance and
tolerance which threatens to kill millions and unravel our current approach to medicine in the
process, unless we find a radical solution.
 To this end, we have identified a potential antibiotic target—the bacterial SOS response.
This response to genotoxic stress is conserved across bacteria and has been connected to
resistance and tolerance mechanisms, including horizontal gene transfer, mutagenesis, and cell
division arrest. Transcription of SOS genes is suppressed by the repressor-protease LexA, which
cleaves upon interaction with filamentous protein RecA* to expose the SOS promoter region. A
previous high throughput screen identified a potent inhibitor of LexA cleavage. We propose a
study to improve this inhibitor and better understand its action and effects. Using a preliminary
structure-activity relationship (SAR) study as a guide, we have designed a library of 22-25 analogs
for a more in-depth SAR campaign, including analogs specifically designed to overcome potential
efflux challenges. Additionally, we have proposed peptide fragments with covalent traps to mimic
the native substrate of the LexA protease and irreversibly inhibit its function. Using our most potent
inhibitors, we will investigate the downstream biological effects of LexA inhibition, including
acquired antibiotic resistance and biofilm formation. We also plan to use photoaffinity probes to
identify the inhibitor binding site and orientation within the protein. The uniquely interdisciplinary
approach of this proposal will elucidate the mechanism of these inhibitors and will lay the
groundwork for a novel strategy to address the resistance and tolerance crisis.

## Key facts

- **NIH application ID:** 10067775
- **Project number:** 1F31AI152459-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Ana V Cheng
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-06-15 → 2023-06-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067775

## Citation

> US National Institutes of Health, RePORTER application 10067775, Inhibition of the Bacterial LexA Repressor-Protease to Halt SOS Response-Mediated Resistance and Biofilm Formation (1F31AI152459-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10067775. Licensed CC0.

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