title: Blocking yersiniabactin import attenuates extraintestinal pathogenic Escherichia coli in cystitis and pyelonephritis and represents a novel target to prevent urinary tract infection.
abstract: The emergence and spread of extended-spectrum beta-lactamases and carbapenemases among common bacterial pathogens are threatening our ability to treat routine hospital- and community-acquired infections. With the pipeline for new antibiotics virtually empty, there is an urgent need to develop novel therapeutics. Bacteria require iron to establish infection, and specialized pathogen-associated iron acquisition systems like yersiniabactin, common among pathogenic species in the family Enterobacteriaceae, including multidrug-resistant Klebsiella pneumoniae and pathogenic Escherichia coli, represent potentially novel therapeutic targets. Although the yersiniabactin system was recently identified as a vaccine target for uropathogenic E. coli (UPEC)-mediated urinary tract infection (UTI), its contribution to UPEC pathogenesis is unknown. Using an E. coli mutant (strain 536ΔfyuA) unable to acquire yersiniabactin during infection, we established the yersiniabactin receptor as a UPEC virulence factor during cystitis and pyelonephritis, a fitness factor during bacteremia, and a surface-accessible target of the experimental FyuA vaccine. In addition, we determined through transcriptome sequencing (RNA-seq) analyses of RNA from E. coli causing cystitis in women that iron acquisition systems, including the yersiniabactin system, are highly expressed by bacteria during natural uncomplicated UTI. Given that yersiniabactin contributes to the virulence of several pathogenic species in the family Enterobacteriaceae, including UPEC, and is frequently associated with multidrug-resistant strains, it represents a promising novel target to combat antibiotic-resistant infections.
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Ariel R
authors.initials: AR
authors.lastname: Brumbaugh
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Sara N
authors.initials: SN
authors.lastname: Smith
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Sargurunathan
authors.initials: S
authors.lastname: Subashchandrabose
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Himpsl
authors.affiliation: Department of Microbiology and Immunology, Institute for Genome Sciences, School of Medicine, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Tracy H
authors.initials: TH
authors.lastname: Hazen
authors.affiliation: Department of Microbiology and Immunology, Institute for Genome Sciences, School of Medicine, University of Maryland, Baltimore, Maryland, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Rasko
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA hmobley@umich.edu.
authors.forename: Harry L T
authors.initials: HL
authors.lastname: Mobley
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001428:Bacterial Vaccines / Q000276:immunology; D003556:Cystitis / Q000382:microbiology / Q000517:prevention & control*; D004927:Escherichia coli Infections / Q000276:immunology; D029968:Escherichia coli Proteins / Q000235:genetics* / Q000276:immunology; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D010636:Phenols / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D011704:Pyelonephritis / Q000382:microbiology / Q000517:prevention & control*; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000276:immunology; D013844:Thiazoles / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D014552:Urinary Tract Infections / Q000382:microbiology / Q000517:prevention & control; D056689:Uropathogenic Escherichia coli / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*
chemical_list: D000911:Antibodies, Monoclonal; D001428:Bacterial Vaccines; D029968:Escherichia coli Proteins; C527466:FyuA protein, E coli; D010636:Phenols; D011956:Receptors, Cell Surface; D013844:Thiazoles; C104398:yersiniabactin