title: The Genotoxin Colibactin Is a Determinant of Virulence in Escherichia coli K1 Experimental Neonatal Systemic Infection.
abstract: Escherichia coli strains expressing the K1 capsule are a major cause of sepsis and meningitis in human neonates. The development of these diseases is dependent on the expression of a range of virulence factors, many of which remain uncharacterized. Here, we show that all but 1 of 34 E. coli K1 neonatal isolates carried clbA and clbP, genes contained within the pks pathogenicity island and required for the synthesis of colibactin, a polyketide-peptide genotoxin that causes genomic instability in eukaryotic cells by induction of double-strand breaks in DNA. Inactivation of clbA and clbP in E. coli A192PP, a virulent strain of serotype O18:K1 that colonizes the gastrointestinal tract and translocates to the blood compartment with very high frequency in experimental infection of the neonatal rat, significantly reduced the capacity of A192PP to colonize the gut, engender double-strand breaks in DNA, and cause invasive, lethal disease. Mutation of clbA, which encodes a pleiotropic enzyme also involved in siderophore synthesis, impacted virulence to a greater extent than mutation of clbP, encoding an enzyme specific to colibactin synthesis. Restoration of colibactin gene function by complementation reestablished the fully virulent phenotype. We conclude that colibactin contributes to the capacity of E. coli K1 to colonize the neonatal gastrointestinal tract and to cause invasive disease in the susceptible neonate.
authors.affiliation: University College London School of Pharmacy, London, United Kingdom.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: McCarthy
authors.affiliation: UMR1043 Inserm, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France USC 1360 INRA, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France UMR 5282 CNRS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Martin
authors.affiliation: UMR1043 Inserm, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France USC 1360 INRA, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France UMR 5282 CNRS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Cloup
authors.affiliation: London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Stabler
authors.affiliation: UMR1043 Inserm, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France USC 1360 INRA, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France UMR 5282 CNRS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France CHU Toulouse, Hôpital Purpan, Service de Bactériologie-Hygiène, Toulouse, France eric.oswald@inserm.fr peter.taylor@ucl.ac.uk.
authors.forename: Eric
authors.initials: E
authors.lastname: Oswald
authors.affiliation: University College London School of Pharmacy, London, United Kingdom eric.oswald@inserm.fr peter.taylor@ucl.ac.uk.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Taylor
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000235:genetics / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000235:genetics / Q000378:metabolism*; D044404:Genomic Islands / Q000235:genetics; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D061065:Polyketides / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D051381:Rats; D017208:Rats, Wistar; D014774:Virulence / Q000502:physiology
chemical_list: D010455:Peptides; D061065:Polyketides; C569566:colibactin