# Small molecule inhibitors for the study of colibactin-induced carcinogenesis by gut microbes

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

## Abstract

PROJECT SUMMARY/ABSTRACT
 Colorectal cancer (CRC) is currently the second leading cause of cancer deaths in the United States
and, as of 2018, shows an increasing mortality rate in younger age groups. The reason for this rise in mortality
has not been fully explained and highlights the urgent need to better understand the causes and risk factors for
CRC and develop novel strategies for its prevention and treatment. A growing body of evidence has implicated
members of the human gut microbiome as potential drivers of CRC development. In particular, bacteria that
produce a small molecule genotoxin known as colibactin may be key players in this process. Colibactin is
produced by both commensal and pathogenic organisms which harbor the pks genomic island. Numerous
studies have shown that transient infection of mammalian cells with pks+ E. coli leads to DNA crosslinking,
DNA double-strand breaks, chromosomal instability, and senescence. Clinical studies have shown that pks+
bacteria are more prevalent in patients with CRC (~68%) and IBD (~40%) in comparison to healthy controls
(21%) and are more abundant in tumor tissue biopsies than those from adjacent healthy tissue. In animal
models, colonization with pks+ E. coli in a mouse model of CRC leads to increased tumor load relative to mice
colonized with non-colibactin-producers. In perhaps the most direct evidence of colibactin’s carcinogenic
potential, recent work has also shown that when mice are colonized with pks+ E. coli, colibactin directly
alkylates DNA in gut epithelial cells, resulting in the formation of DNA adducts. Together, this evidence
suggests that exposure to colibactin may increase risk for, or accelerate the development of, CRC via the
mutagenic effects of DNA alkylation and crosslinking by colibactin. Despite this, no viable therapeutic strategy
has emerged to prevent colibactin exposure, and no tools exist to study the effects of this pathway in the
context of a complex, healthy gut-microbial community. This proposal aims to address these knowledge gaps
by developing potent and specific small molecule inhibitors of colibactin biosynthesis. Such tool compounds
will enable a more detailed study of how colibactin contributes to CRC progression and allow us to test the
hypothesis that blocking colibactin production by pks+ bacteria using small molecules can lower the risk of
developing CRC for the host. This research will both to explore a novel molecular target for therapeutic
intervention in CRC development, as well as provide the wider scientific community with tools that will enable a
more precise study of the impacts of small molecule toxins from commensal microbes on human health.

## Key facts

- **NIH application ID:** 9907706
- **Project number:** 1F31CA247069-01
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Matthew Robert Volpe
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9907706

## Citation

> US National Institutes of Health, RePORTER application 9907706, Small molecule inhibitors for the study of colibactin-induced carcinogenesis by gut microbes (1F31CA247069-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9907706. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*