title: Aerobactin, but not yersiniabactin, salmochelin, or enterobactin, enables the growth/survival of hypervirulent (hypermucoviscous) Klebsiella pneumoniae ex vivo and in vivo.
abstract: The siderophore aerobactin is the dominant siderophore produced by hypervirulent Klebsiella pneumoniae (hvKP) and was previously shown to be a major virulence factor in systemic infection. However, strains of hvKP commonly produce the additional siderophores yersiniabactin, salmochelin, and enterobactin. The roles of these siderophores in hvKP infection have not been optimally defined. To that end, site-specific gene disruptions were created in hvKP1 (wild type), resulting in the generation of hvKP1ΔiucA (aerobactin deficient), hvKP1ΔiroB (salmochelin deficient), hvKP1ΔentB (enterobactin and salmochelin deficient), hvKP1Δirp2 (yersiniabactin deficient), and hvKP1ΔentBΔirp2 (enterobactin, salmochelin, and yersiniabactin deficient). The growth/survival of these constructs was compared to that of their wild-type parent hvKP1 ex vivo in human ascites fluid, human serum, and human urine and in vivo in mouse systemic infection and pulmonary challenge models. Interestingly, in contrast to aerobactin, the inability to produce enterobactin, salmochelin, or yersiniabactin individually or in combination did not decrease the ex vivo growth/survival in human ascites or serum or decrease virulence in the in vivo infection models. Surprisingly, none of the siderophores increased growth in human urine. In human ascites fluid supplemented with exogenous siderophores, siderophores increased the growth of hvKP1ΔiucA, with the relative activity being enterobactin > aerobactin > yersiniabactin > salmochelin, suggesting that the contribution of aerobactin to virulence is dependent on both innate biologic activity and quantity produced. Taken together, these data confirm and extend a role for aerobactin as a critical virulence factor for hvKP. Since it appears that aerobactin production is a defining trait of hvKP strains, this factor is a potential antivirulence target.
authors.affiliation: Veterans Administration Western New York Healthcare System, Buffalo, New York, USA Department of Medicine, University at Buffalo-State University of New York, Buffalo, New York, USA Department of Microbiology and Immunology, University at Buffalo-State University of New York, Buffalo, New York, USA The Witebsky Center for Microbial Pathogenesis, University at Buffalo-State University of New York, Buffalo, New York, USA trusso@acsu.buffalo.edu.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Russo
authors.affiliation: Veterans Administration Western New York Healthcare System, Buffalo, New York, USA Department of Medicine, University at Buffalo-State University of New York, Buffalo, New York, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Olson
authors.affiliation: Veterans Administration Western New York Healthcare System, Buffalo, New York, USA Department of Medicine, University at Buffalo-State University of New York, Buffalo, New York, USA.
authors.forename: Ulrike
authors.initials: U
authors.lastname: MacDonald
authors.affiliation: Veterans Administration Western New York Healthcare System, Buffalo, New York, USA Department of Medicine, University at Buffalo-State University of New York, Buffalo, New York, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Beanan
authors.affiliation: Veterans Administration Western New York Healthcare System, Buffalo, New York, USA Department of Anesthesiology, University at Buffalo-State University of New York, Buffalo, New York, USA Department of Pathology and Anatomical Sciences, University at Buffalo-State University of New York, Buffalo, New York, USA The Witebsky Center for Microbial Pathogenesis, University at Buffalo-State University of New York, Buffalo, New York, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Davidson
mesh_terms: D000818:Animals; D004758:Enterobactin / Q000031:analogs & derivatives* / Q000378:metabolism*; D005960:Glucosides / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism*; D007710:Klebsiella Infections / Q000382:microbiology*; D007711:Klebsiella pneumoniae / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism / Q000472:pathogenicity; D008297:Male; D051379:Mice; D050296:Microbial Viability / Q000187:drug effects; D010636:Phenols / Q000378:metabolism*; D017262:Siderophores / Q000378:metabolism*; D013844:Thiazoles / Q000378:metabolism*; D014774:Virulence; D055815:Young Adult
chemical_list: D005960:Glucosides; D006877:Hydroxamic Acids; D010636:Phenols; D017262:Siderophores; D013844:Thiazoles; C508254:salmochelin S4; C104398:yersiniabactin; C031819:aerobactin; D004758:Enterobactin