title: Novel antimicrobial peptide prevents C. rodentium infection in C57BL/6 mice by enhancing acid-induced pathogen killing.
abstract: Citrobacter rodentium is a Gram-negative, murine-specific enteric pathogen that infects epithelial cells in the colon. It is closely related to the clinically relevant human pathogen, enterohemorrhagic Escherichia coli (EHEC), a leading cause of haemorrhagic colitis and haemolytic uremic syndrome. We have previously reported that a novel antimicrobial peptide, wrwycr, compromises bacterial DNA repair and significantly reduces the survival of acid-stressed EHEC, suggesting an antimicrobial strategy for targeting the survival of ingested EHEC. This study examines the impact of peptide pretreatment on survival of the closely related murine pathogen, C. rodentium, before and after acid stress, using both in vitro and in vivo investigations. Peptide pretreatment of C. rodentium significantly and dramatically increases acid-stress-induced killing in a peptide-dose-dependent and time-dependent manner. Reduction in survival rates after brief pretreatment with peptide (25-65 µM) followed by 1 h at pH 3.5 ranges from 6 to 8 log fold relative to untreated C. rodentium, with no detectable bacteria after 65 µM peptide-acid treatment. Using a C57BL/6 mouse model of infection, peptide pretreatment of C. rodentium with wrwycr prior to orogastric gavage eliminates evidence of infection based on C. rodentium colonization levels, faecal scores, colonic histology, faecal microbiome and visual observation of overall animal health. These findings provide compelling evidence for the role of the peptide wrwycr as a potential strategy to control the growth and colonization of enteric pathogens.
authors.affiliation: Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada.
authors.forename: Tracy
authors.initials: T
authors.lastname: Lackraj
authors.affiliation: Cell Biology Program, Research Institute, Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
authors.forename: Kathene
authors.initials: K
authors.lastname: Johnson-Henry
authors.affiliation: Cell Biology Program, Research Institute, Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Sherman
authors.affiliation: Center for Microbial Pathogenesis, Nationwide Children's Hospital, Ohio State University, Columbus, OH, USA.
authors.forename: Steve D
authors.initials: SD
authors.lastname: Goodman
authors.affiliation: Department of Biology, Viral Information Institute, San Diego State University, San Diego, CA, USA.
authors.forename: Anca M
authors.initials: AM
authors.lastname: Segall
authors.affiliation: Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada.|Molecular Structure and Function Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada.|Faculty of Dentistry, University of Toronto, Toronto, ON, Canada.
authors.forename: Debora
authors.initials: D
authors.lastname: Barnett Foster
mesh_terms: D000143:Acids / Q000494:pharmacology*; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000008:administration & dosage*; D044082:Citrobacter rodentium / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D003106:Colon / Q000382:microbiology; D004756:Enterobacteriaceae Infections / Q000382:microbiology / Q000517:prevention & control*; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000143:Acids; D023181:Antimicrobial Cationic Peptides