Two Polyketides Intertwined in Complex Regulation: Posttranscriptional CsrA-Mediated Control of Colibactin and Yersiniabactin Synthesis in Escherichia coli

Rehm, Nadine; Wallenstein, Alexander; Keizers, Marla; Homburg, Stefan; Magistro, Giuseppe; Chagneau, Camille V.; Klimek, Hanna; Revelles, Olga; Helloin, Emmanuelle; Putze, Johannes; Nougayrède, Jean-Philippe; Schubert, Sören; Oswald, Éric; Dobrindt, Ulrich

doi:10.1128/mbio.03814-21

Cited by 11 publications

(19 citation statements)

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“…These BGCs are present across diverse genera like Escherichia , Klebsiella , Enterobacter , and Citrobacter . Recent studies have shown a tight correlation between colibactin and yersiniabactin evolution and expression [ [37] , [38] , [39] , [40] ]. The yersiniabactin BGC is observed to be present whenever colibactin is present across genera as also seen earlier [ 41 ], with exception of E. coli BCE049 and K. pneumoniae 11492 that only contained colibactin BGC.…”

Section: Resultsmentioning

confidence: 99%

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Pangenome analysis of Enterobacteria reveals richness of secondary metabolite gene clusters and their associated gene sets

Mohite

Lloyd

Monk

et al. 2022

Synthetic and Systems Biotechnology

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Section: Resultsmentioning

confidence: 99%

“…The gene ripA_2 is associatively present in all colibactin-containing strains along with the known transcriptional regulator ybtA of the AraC-like family. The ybtA gene expression is shown to be required under iron limiting conditions to initiate expression polyketides [ 37 ].…”

Section: Resultsmentioning

confidence: 99%

Pangenome analysis of Enterobacteria reveals richness of secondary metabolite gene clusters and their associated gene sets

Mohite

Lloyd

Monk

et al. 2022

Synthetic and Systems Biotechnology

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“…It has been repeatedly reported that DNA damage was observed in enterocytes of rats and mice colonized or force-fed with different strains of E. coli pks+ (NC101, 192PP, M1/5, SP15, Nissle 1917) (13,15,16,18,39). Keeping in mind that colibactin production is also regulated by numerous environmental cues such as iron, polyamines, and carbon sources (20)(21)(22), the physiological hypoxia at the surface of the epithelium could constitute a favorable environment for colibactin production and activity. Other low oxygen intestinal compartments could favor colibactin production, such as the stem cells that reside in a hypoxic niche (as low as 1% O2) at the bottom of the crypt (40).…”

Section: Discussionmentioning

confidence: 99%

Oxygen concentration modulates colibactin production

Bossuet-Greif

Guyonnet

Chagneau

et al. 2022

Preprint

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Commensal and extra-intestinal pathogenic strains of E. coli frequently harbor the pks genomic island encoding the synthesis of colibactin, a genotoxic metabolite. The gut and infected tissue are low oxygen environments, but it is not known whether oxygen modulates production of the genotoxin. Here, we report on the serendipitous observation that oxygenation of the bacterial culture strongly modulates the autotoxicity of a E. coli pks clbS mutant deficient for colibactin self-protection system. We further found that DNA damaging activity by pks+ E. coli decreased with increasing oxygen concentration in the medium. Similarly, the level of the N-myristoyl-D-Asn metabolite that is released during the final step of colibactin synthesis decreased with increasing oxygen concentration. The activity of the promoter of a gene for the colibactin synthase ClbB, as well as its transcription, were maximal under anoxic conditions, but decreased with increased oxygen concentration. Thus, colibactin synthesis is inhibited by oxygen, suggesting that the pks biosynthetic pathway is adapted to the anoxic intestinal lumen and to the hypoxic infected or tumor tissue.

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“…The assay was performed as previously described [39]. Briefly, linearized plasmid DNA was generated by digestion of pUC19 plasmid with BamHI (New England Biolabs).…”

Section: Methodsmentioning

confidence: 99%

The therapeutic potential of D-Serine in reducing expression of the cytopathic genotoxin colibactin

Hallam

O’Boyle

Turner

et al. 2022

Preprint

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Some Escherichia coli strains belonging mainly to the B2 phylogroup 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. Moreover, production of colibactin has been implicated in the development of colorectal cancer. In this study, we demonstrate the inhibitory effect of D-Serine on the expression of the pks island in two colibactin-producing strains, CFT073 and Nissle 1917, and determine the implications for cytopathic effects on host cells. To investigate the specificity of the inhibitory effect of D-Serine, we also tested a comprehensive panel of proteinogenic L-amino acids and corresponding D-enantiomers for their ability to modulate clbB transcription using RT-qPCR. Several D-amino acids exhibited the ability to inhibit expression of clbB, with D-Serine exerting the strongest repressing activity (3.81-fold in CFT073; 3.80-fold in Nissle 1917) 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 therapeutic potential to prevent colibactin-associated disease.

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Two Polyketides Intertwined in Complex Regulation: Posttranscriptional CsrA-Mediated Control of Colibactin and Yersiniabactin Synthesis in Escherichia coli

Abstract: Secondary metabolite expression is a widespread strategy among bacteria to improve their fitness in habitats where they constantly compete for resources with other bacteria. The production of secondary metabolites is associated with a metabolic and energetic burden.

Cited by 11 publications

References 99 publications

Pangenome analysis of Enterobacteria reveals richness of secondary metabolite gene clusters and their associated gene sets

Pangenome analysis of Enterobacteria reveals richness of secondary metabolite gene clusters and their associated gene sets

Oxygen concentration modulates colibactin production

The therapeutic potential of D-Serine in reducing expression of the cytopathic genotoxin colibactin

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