D-Serine reduces the expression of the cytopathic genotoxin colibactin

Authors:

Jennifer C. Hallam1,#, Sofia Sandalli1,#, Iris Floria1, Natasha C. A. Turner1, Min Tang-Fichaux2, Eric Oswald2,3, Nicky O’Boyle1,4 and Andrew J. Roe1

doi: 10.15698/mic2023.03.793
Volume 10, pp. 63 to 77, published 06/03/2023.

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Affiliations:

1 School of Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom.

2 IRSD, INSERM, INRAE, Université de Toulouse, ENVT, Toulouse, France.

3 CHU Toulouse, Hôpital Purpan, Service de Bactériologie-Hygiène, Toulouse, France.

4 School of Microbiology, University College Cork, National University of Ireland, Cork, Ireland.

# JCH and SS contributed equally to this work.

Keywords: 

E. coli, colibactin, expression, genotoxin, cell cycle.

Corresponding Author(s):

Andrew J. Roe, School of Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom; Andrew.roe@glasgow.ac.uk Nicky O’Boyle, School of Microbiology, University College Cork, National University of Ireland, Cork, Ireland; NOboyle@ucc.ie

Conflict of interest statement:

All authors declare that they have no conflicts of interest.

Please cite this article as:

Jennifer C. Hallam, Sofia Sandalli, Iris Floria, Natasha C. A. Turner, Min Tang-Fichaux, Eric Oswald, Nicky O’Boyle and Andrew J. Roe (2023). D-Serine reduces the expression of the cyto-pathic genotoxin colibactin. Microbial Cell 10(3): 63-77. doi: 10.15698/mic2023.03.793

© 2023 Hallam et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduc-tion in any medium, provided the original author and source are acknowledged.

Abstract:

Some Escherichia coli strains harbour the pks island, a 54 kb genomic island encoding the biosynthesis genes for a genotoxic compound named colibactin. In eukaryotic cells, colibactin can induce DNA damage, cell cycle arrest and chromosomal instability. Production of colibactin has been implicated in the development of colorectal cancer (CRC). In this study, we demonstrate the inhibitory effect of D-Serine on the expression of the pks island in both prototypic and clinically-associated colibactin-producing strains and determine the implications for cytopathic effects on host cells. We also tested a comprehensive panel of proteinogenic L-amino acids and corresponding D-enantiomers for their ability to modulate clbB transcription. Whilst several D-amino acids exhibited the ability to inhibit expression of clbB, D-Serine exerted the strongest repressing activity (>3.8-fold) and thus, we focussed additional experiments on D-Serine. To investigate the cellular effect, we investigated if repression of colibactin by D-Serine could reduce the cytopathic responses normally observed during infection of HeLa cells with pks+ strains. Levels of γ-H2AX (a marker of DNA double strand breaks) were reduced 2.75-fold in cells infected with D-Serine treatment. Moreover, exposure of pks+ E. coli to D-Serine during infection caused a reduction in cellular senescence that was observable at 72 h post infection. The recent finding of an association between pks-carrying commensal E. coli and CRC, highlights the necessity for the development of colibactin targeting therapeutics. Here we show that D-Serine can reduce expression of colibactin, and inhibit downstream cellular cytopathy, illuminating its potential to prevent colibactin-associated disease.