title: Amphiphilic tobramycins with immunomodulatory properties.
abstract: Amphiphilic aminoglycosides (AAGs) are an emerging source of antibacterials to combat infections caused by antibiotic-resistant bacteria. Mode-of-action studies indicate that AAGs predominately target bacterial membranes, thereby leading to depolarization and increased permeability. To assess whether AAGs also induce host-directed immunomodulatory responses, we determined the AAG-dependent induction of cytokines in macrophages in the absence or presence of lipopolysaccharide (LPS). Our results show for the first time that AAGs can boost the innate immune response, specifically the recruitment of immune cells such as neutrophils required for the resolution of infections. Moreover, AAGs can selectively control inflammatory responses induced in the presence of endotoxins to prevent septic shock. In conclusion, our study demonstrates that AAGs possess multifunctional properties that combine direct antibacterial activity with host-directed clearance effects reminiscent of those of host-defense peptides.
authors.affiliation: Department of Chemistry, University of Manitoba, Winnipeg, MB, R3T 2N2 (Canada).
authors.forename: Goutam
authors.initials: G
authors.lastname: Guchhait
authors.affiliation: Department of Internal Medicine and Immunology, University of Manitoba, Winnipeg, MB, R3T 2N2 (Canada).
authors.forename: Anthony
authors.initials: A
authors.lastname: Altieri
authors.affiliation: Department of Chemistry, University of Manitoba, Winnipeg, MB, R3T 2N2 (Canada).
authors.forename: Balakishan
authors.initials: B
authors.lastname: Gorityala
authors.affiliation: Department of Chemistry, University of Manitoba, Winnipeg, MB, R3T 2N2 (Canada).
authors.forename: Xuan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Chemistry, University of Manitoba, Winnipeg, MB, R3T 2N2 (Canada).
authors.forename: Brandon
authors.initials: B
authors.lastname: Findlay
authors.affiliation: Department of Medical Microbiology and Medicine, Health Science Centre, Winnipeg, Manitoba, R3T 1R9 (Canada).
authors.forename: George G
authors.initials: GG
authors.lastname: Zhanel
authors.affiliation: Department of Internal Medicine and Immunology, University of Manitoba, Winnipeg, MB, R3T 2N2 (Canada).
authors.forename: Neeloffer
authors.initials: N
authors.lastname: Mookherjee
authors.affiliation: Department of Chemistry, University of Manitoba, Winnipeg, MB, R3T 2N2 (Canada). Frank.Schweizer@umanitoba.ca.
authors.forename: Frank
authors.initials: F
authors.lastname: Schweizer
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D007155:Immunologic Factors / Q000737:chemistry / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D014031:Tobramycin / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; D007155:Immunologic Factors; D008070:Lipopolysaccharides; D014031:Tobramycin
keywords: aminoglycosides; amphiphiles; antibiotics; drug design; host-defense peptides