# The Molecular Basis for the Bacterial SOS Signal

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $309,925

## Abstract

PROJECT ABSTRACT
 Infections due to antibiotic-resistant bacteria are becoming costlier and deadlier, and drug development
efforts to expand our antibiotic arsenal cannot keep up with the rapid pace of bacterial evolution. New
approaches are needed to address this pressing problem. Targeting the SOS response, a key mechanism by
which bacteria adapt to antibiotics and evolve resistance, is an emerging approach with significant promise.
The SOS response is a network of genes that are turned on when the DNA damage ‘SOS signal’ is activated.
Across many bacterial pathogens, SOS pathway effectors have been shown to serve critical roles in the
evasion of antibiotics, including heightened mutation rates, transfer of mobile resistance genes, and phenotypic
conversion to antibiotic-resistant states. These findings highlight the potential for small molecule SOS inhibitors
to function as antibiotic adjuvants, preventing bacteria from adapting or evolving resistance to antibiotics. The
core of the ‘SOS signal’ is well-conserved across pathogens and is encapsulated in the interaction of two
proteins, LexA and RecA. RecA binds to DNA fragments to form activated RecA* and this complex stimulates
the auto-proteolysis of LexA. This process is pivotal to turning on the SOS response as LexA is a repressor of
the SOS response. Upon auto-proteolysis, LexA is no longer able to function as a repressor and the SOS
response is activated. The overall goal of this project is to reveal how the ‘SOS signal’ is generated, with a
particular focus on three major unknowns: 1) the molecular composition of the complex between LexA and
RecA*, 2) how conformational dynamics and allosteric modulation permits transmission of the signal between
these two proteins, and 3) how the generation of the SOS signal can be inhibited by small molecules. To
address these unresolved and important questions, protein engineering will be employed to reduce the SOS
signal to its minimal components; novel minimally-perturbing fluorescent probes will be utilized to report on
structural dynamics; and newly-discovered small molecule SOS antagonists will be exploited to dissect the
critical steps in generation of the SOS signal. This proposal offers fundamental biochemical and biophysical
insights into the conserved LexA/RecA* signaling axis and will fuel a novel approach to the problem of
antibiotic resistance, rooted in targeting an adaptive pathway that promotes evasion and the evolution of
resistance itself.

## Key facts

- **NIH application ID:** 9872192
- **Project number:** 5R01GM127593-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Rahul Manu Kohli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $309,925
- **Award type:** 5
- **Project period:** 2018-05-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9872192

## Citation

> US National Institutes of Health, RePORTER application 9872192, The Molecular Basis for the Bacterial SOS Signal (5R01GM127593-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9872192. Licensed CC0.

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