Interplay between Siderophores and Colibactin Genotoxin Biosynthetic Pathways in Escherichia coli
Open accessAbstract
In Escherichia coli, the biosynthetic pathways of several small iron-scavenging molecules known as siderophores (enterobactin, salmochelins and yersiniabactin) and of a genotoxin (colibactin) are known to require a 4'-phosphopantetheinyl transferase (PPTase). Only two PPTases have been clearly identified: EntD and ClbA. The gene coding for EntD is part of the core genome of E. coli, whereas ClbA is encoded on the pks pathogenicity island which codes for colibactin. Interestingly, the pks island is physically associated with the high pathogenicity island (HPI) in a subset of highly virulent E. coli strains. The HPI carries the gene cluster required for yersiniabactin synthesis except for a gene coding its cognate PPTase. Here we investigated a potential interplay between the synthesis pathways leading to the production of siderophores and colibactin, through a functional interchangeability between EntD and ClbA. We demonstrated that ClbA could contribute to siderophores synthesis. Inactivation of both entD and clbA abolished the virulence of extra-intestinal pathogenic E. coli (ExPEC) in a mouse sepsis model, and the presence of either functional EntD or ClbA was required for the survival of ExPEC in vivo. This is the first report demonstrating a connection between multiple phosphopantetheinyl-requiring pathways leading to the biosynthesis of functionally distinct secondary metabolites in a given microorganism. Therefore, we hypothesize that the strict association of the pks island with HPI has been selected in highly virulent E. coli because ClbA is a promiscuous PPTase that can contribute to the synthesis of both the genotoxin and siderophores. The data highlight the complex regulatory interaction of various virulence features with different functions. The identification of key points of these networks is not only essential to the understanding of ExPEC virulence but also an attractive and promising target for the development of anti-virulence therapy strategies.
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In germ-free mice administered Nissle 1917, intestinal epithelial cells showed evidence of DNA damage, which was not observed with clbA or clbP mutants.
“In germ-free mice administered with Nissle 1917, intestinal epithelial cells showed evidence of DNA damage [132], which was not observed when mice were inoculated with variants of Nissle 1917 carrying mutations in clbA or clbP”
From Selection, Comparative Genomics, and Potential Probiotic Features of Escherichia coli 5C, a pks-Negative Strain Isolated from Healthy Infant Donor Feces (2026) · cites this paper as [133]
The Mouse sepsis model methods describe footpad injection of ExPEC strains, not administration of Nissle 1917 to germ-free mice. The Results section reports DNA-damage measurements in HeLa cells, but our copy does not report intestinal epithelial DNA damage in germ-free mice given Nissle 1917 (searched: Nissle 1917, germ-free mice, clbP). (LLM, conf=0.77)
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“…Nissle 1917, intestinal epithelial cells showed evidence of DNA damage [132], which was not observed when mice were inoculated with variants of Nissle 1917 carrying mutations in clbA or clbP , genes encoded within the pks cluster and which are directly involved in colibactin synthesis [47, 133].”
- Authors
- Martin, P., Marcq, I., Magistro, G., Penary, M., Garcie, C., Payros, D., Boury, M., Olier, M., Nougayrède, J.-P., Audebert, M., Chalut, C., Schubert, S., & Oswald, E.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Max-von-Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie (DE)
- Toxicologie Alimentaire (FR)
- Université Toulouse III - Paul Sabatier (FR)
- Université de Picardie Jules Verne (FR)
- ORCID
- Venue
- PLoS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-07-11
- Volume
- 9
- Issue
- 7
- Pages
- e1003437
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC3708854
- OpenAlex
- W2049047304
- Cited by
- 138
- References
- 53
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 10 · 2023: 5 · 2022: 18 · 2021: 23 · 2020: 10 · 2019: 11 · 2018: 8 · 2017: 11 · 2016: 12 · 2015: 8 · 2014: 4 · 2013: 3
- FWCI
- 6.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- HAL Portal Artxiker (Hindustan Aeronautics Limited (India)) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Agence Nationale de la Recherche
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Escherichia coli research studies
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- siderophores, colibactin, 4'-phosphopantetheinyl transferase, enterobactin, salmochelin, yersiniabactin, high-pathogenicity island, extraintestinal pathogenic Escherichia coli, virulence, sepsis, anti-virulence therapy, iron acquisition
- MeSH terms
- Animals, Bacterial Proteins, Enterobactin, Escherichia coli, Escherichia coli Infections, Female, Glycopeptides, Isoenzymes, Mice, Inbred C57BL, Mutagens, Mutation, Peptides, Phenols, Thiazoles, Virulence, Siderophores, Gene Deletion, Transferases (Other Substituted Phosphate Groups), Sepsis, Escherichia coli Proteins, Genomic Islands, Mice, Polyketides
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