title: Interplay between siderophores and colibactin genotoxin biosynthetic pathways in Escherichia coli.
abstract: 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.
authors.affiliation: Inserm, UMR1043, Toulouse, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Martin
authors.forename: Ingrid
authors.initials: I
authors.lastname: Marcq
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Magistro
authors.forename: Marie
authors.initials: M
authors.lastname: Penary
authors.forename: Christophe
authors.initials: C
authors.lastname: Garcie
authors.forename: Delphine
authors.initials: D
authors.lastname: Payros
authors.forename: Michèle
authors.initials: M
authors.lastname: Boury
authors.forename: Maïwenn
authors.initials: M
authors.lastname: Olier
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Nougayrède
authors.forename: Marc
authors.initials: M
authors.lastname: Audebert
authors.forename: Christian
authors.initials: C
authors.lastname: Chalut
authors.forename: Sören
authors.initials: S
authors.lastname: Schubert
authors.forename: Eric
authors.initials: E
authors.lastname: Oswald
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D004758:Enterobactin / Q000031:analogs & derivatives / Q000096:biosynthesis; D004926:Escherichia coli / Q000201:enzymology / Q000378:metabolism* / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000378:metabolism / Q000382:microbiology; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D044404:Genomic Islands; D006020:Glycopeptides / Q000096:biosynthesis; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000378:metabolism*; D009154:Mutation; D010455:Peptides / Q000378:metabolism*; D010636:Phenols / Q000378:metabolism; D061065:Polyketides / Q000378:metabolism*; D018805:Sepsis / Q000378:metabolism / Q000382:microbiology; D017262:Siderophores / Q000096:biosynthesis*; D013844:Thiazoles / Q000378:metabolism; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism*; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D006020:Glycopeptides; D007527:Isoenzymes; D009153:Mutagens; D010455:Peptides; D010636:Phenols; D061065:Polyketides; D017262:Siderophores; D013844:Thiazoles; C569566:colibactin; C082662:phosphopantetheinyl transferase; C104398:yersiniabactin; D004758:Enterobactin; D017855:Transferases (Other Substituted Phosphate Groups)