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Angew Chem Int Ed Engl. 2015 May 18;54(21):6278-82. doi: 10.1002/anie.201500598. Epub 2015 Apr 1.

Amphiphilic tobramycins with immunomodulatory properties.

Author information

1
Department of Chemistry, University of Manitoba, Winnipeg, MB, R3T 2N2 (Canada).
2
Department of Internal Medicine and Immunology, University of Manitoba, Winnipeg, MB, R3T 2N2 (Canada).
3
Department of Medical Microbiology and Medicine, Health Science Centre, Winnipeg, Manitoba, R3T 1R9 (Canada).
4
Department of Chemistry, University of Manitoba, Winnipeg, MB, R3T 2N2 (Canada). Frank.Schweizer@umanitoba.ca.

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.

KEYWORDS:

aminoglycosides; amphiphiles; antibiotics; drug design; host-defense peptides

PMID:
25847672
DOI:
10.1002/anie.201500598
[Indexed for MEDLINE]

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