# Validating a potential interaction between error-prone polymerases and SSB as a therapeutic target for Mycobacterium tuberculosis

> **NIH NIH R03** · HARVARD MEDICAL SCHOOL · 2021 · $84,500

## Abstract

Project Summary
Tuberculosis, caused by the bacterium Mycobacterium tuberculosis (Mtb), remains a serious global health
threat that kills over a million people per year worldwide. While antibiotic treatments have existed for some
time, they are often not successful. The necessity for an extended treatment course and the development of
resistance to commonly prescribed antibiotics during treatment are major challenges that need to be overcome
to improve patient outcomes.
 Chromosomal mutations due to the action of error-prone DNA polymerases are a major driver of
mutagenesis in Mtb and therefore the emergence of antibiotic resistance. Error-prone polymerases are
involved in a DNA damage tolerance process known as translesion synthesis. Typically, error-prone
polymerases are tightly regulated so that they are not active during DNA replication. However, they become
activated under stress conditions, such as those experienced during antibiotic treatment. In recent work from
our laboratory, we demonstrated that within the model bacterium Escherichia coli, the activation of the error-
prone polymerase Pol IV requires an interaction with single-stranded DNA binding protein (SSB), which acts to
locally concentrate Pol IV near sites of DNA damage. Importantly, ablation of this interaction substantially
reduced Pol IV-mediated translesion synthesis and mutagenesis. In this proposal we will test whether the
three Pol IV homologs in Mtb interact with MtSSB. Next, we will identify mutations that ablate this putative
interaction without affecting other molecular interactions or polymerase activity. Finally, we will introduce these
mutations into Mycobacterium smegmatis, a non-pathogenic model system of Mtb, and test whether these
strains are sensitized to DNA damage agents. If successful, these studies will identify a novel molecular
interaction to potentially target therapeutically to suppress the emergence of antibiotic resistance in Mtb.

## Key facts

- **NIH application ID:** 10189804
- **Project number:** 1R03AI159062-01
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Joseph J. Loparo
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $84,500
- **Award type:** 1
- **Project period:** 2021-03-08 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189804

## Citation

> US National Institutes of Health, RePORTER application 10189804, Validating a potential interaction between error-prone polymerases and SSB as a therapeutic target for Mycobacterium tuberculosis (1R03AI159062-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10189804. Licensed CC0.

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