Deciphering the interplay between the genotoxic and probiotic activities of Escherichia coli Nissle 1917


Autoři: Clémence Massip aff001;  Priscilla Branchu aff001;  Nadège Bossuet-Grief aff001;  Camille V. Chagneau aff001;  Déborah Gaillard aff001;  Patricia Martin aff001;  Michèle Boury aff001;  Thomas Sécher aff001;  Damien Dubois aff001;  Jean-Philippe Nougayrède aff001;  Eric Oswald aff001
Působiště autorů: IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France aff001;  CHU Toulouse, Hôpital Purpan, Service de Bactériologie-Hygiène, Toulouse, France aff002
Vyšlo v časopise: Deciphering the interplay between the genotoxic and probiotic activities of Escherichia coli Nissle 1917. PLoS Pathog 15(9): e32767. doi:10.1371/journal.ppat.1008029
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008029

Souhrn

Although Escherichia coli Nissle 1917 (EcN) has been used therapeutically for over a century, the determinants of its probiotic properties remain elusive. EcN produces two siderophore-microcins (Mcc) responsible for an antagonistic activity against other Enterobacteriaceae. EcN also synthesizes the genotoxin colibactin encoded by the pks island. Colibactin is a virulence factor and a putative pro-carcinogenic compound. Therefore, we aimed to decouple the antagonistic activity of EcN from its genotoxic activity. We demonstrated that the pks-encoded ClbP, the peptidase that activates colibactin, is required for the antagonistic activity of EcN. The analysis of a series of ClbP mutants revealed that this activity is linked to the transmembrane helices of ClbP and not the periplasmic peptidase domain, indicating the transmembrane domain is involved in some aspect of Mcc biosynthesis or secretion. A single amino acid substitution in ClbP inactivates the genotoxic activity but maintains the antagonistic activity. In an in vivo salmonellosis model, this point mutant reduced the clinical signs and the fecal shedding of Salmonella similarly to the wild type strain, whereas the clbP deletion mutant could neither protect nor outcompete the pathogen. The ClbP-dependent antibacterial effect was also observed in vitro with other E. coli strains that carry both a truncated form of the Mcc gene cluster and the pks island. In such strains, siderophore-Mcc synthesis also required the glucosyltransferase IroB involved in salmochelin production. This interplay between colibactin, salmochelin, and siderophore-Mcc biosynthetic pathways suggests that these genomic islands were co-selected and played a role in the evolution of E. coli from phylogroup B2. This co-evolution observed in EcN illustrates the fine margin between pathogenicity and probiotic activity, and the need to address both the effectiveness and safety of probiotics. Decoupling the antagonistic from the genotoxic activity by specifically inactivating ClbP peptidase domain opens the way to the safe use of EcN.

Klíčová slova:

Antibacterials – Bacterial pathogens – Gastrointestinal tract – Islands – Proteases – Probiotics – Salmonella typhimurium – Salmonellosis


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