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Modulation atypique de la biosynthèse de la colibactine, une génotoxine de Escherichia coli, ou comment un îlot génomique est en symbiose avec le chromosome bactérien

Abstract : The pks genomic island codes a complex biosynthetic assembly line that synthetizes the colibactin, a genotoxin produced by some strains of Escherichia coli. This genotoxin generates DNA double-strand breaks in eukaryotic cells both in vitro and in vivo. Colibactin is not a protein, but a secondary metabolite belonging to the chemical family of hybrid polyketide/nonribosomal peptide compounds. Preliminary results from our research team suggested that certain genes of the E. coli core genome (i.e. genes present in all strains of the species) could also be involved in the colibactin production. The main goal of this thesis was to identify non-essential E. coli genes located outside the pks island that are required for colibactin biosynthesis, with the screening of a transposon mutant library. This revealed 29 potential candidate genes, but the project focused specifically on two groups of genes: three genes encoding chaperone proteins, and three genes encoding enzymes involved in polyamines metabolism. The first project highlighted the role of the molecular chaperone HtpG (or Hsp90Ec), the bacterial homolog of eukaryotic heat shock protein 90, in the production of colibactin, but also yersiniabactin, a siderophore (i.e. a bacterial iron uptake system) that belongs to the same chemical family as colibactin. Furthermore, the ClpQ protease was involved in colibactin and yersiniabactin production in combination with Hsp90Ec. These results confirmed the interplay between the biosynthesis of two E. coli virulence factors, colibactin and yersiniabactin. Finally, analysis of the effects of htpG disruption during systemic infection in animals, using rodent models of sepsis and neonatal meningitis, demonstrated the role of the stress-responsive molecular chaperone Hsp90Ec in E. coli virulence. The second project revealed the involvement of polyamines in the biosynthesis of colibactin. A molecular microbiology approach demonstrated that spermidine was the polyamine required for colibactin production. Preliminary results suggested that spermidine could regulate the expression of some pks island genes, and therefore could modulate colibactin production. Further experiments are in progress to elucidate the molecular mechanisms involved in this regulation. Together, the results of this thesis perfectly illustrate the symbiotic integration of a mobile genetic element acquired during evolution into the bacterial chromosome, through several crosstalks allowing the production of virulence factors in E. coli.
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Christophe Garcie. Modulation atypique de la biosynthèse de la colibactine, une génotoxine de Escherichia coli, ou comment un îlot génomique est en symbiose avec le chromosome bactérien. Microbiologie et Parasitologie. Université Paul Sabatier - Toulouse III, 2016. Français. ⟨NNT : 2016TOU30283⟩. ⟨tel-01874812⟩

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