TY - JOUR
T1 - Characterization of a proteolytically stable multifunctional host defense peptidomimetic
AU - Jahnsen, Rasmus D.
AU - Haney, Evan F.
AU - Franzyk, Henrik
AU - Hancock, Robert E.W.
N1 - Funding Information:
We thank Derrick Horne for assistance in the electron microscopy imaging. We thank Ashley Hilchie and Laurence Madera for assistance in blood collection. We thank Fany Reffuveille for providing recommendations for bacterial growth conditions in the crystal violet assay. Finally, we thank Jelena Pistolic for technical assistance. The present work was performed as part of the Danish Centre for Antibiotic Research and Development financed by The Danish Council for Strategic Research (grant no. 09-067075). Funding for research in the lab of R.E.W.H. was provided by the Canadian Institutes of Health Research (CIHR). E.F.H. is supported by a postdoctoral fellowship from the CIHR. R.E.W.H. holds a Canada Research Chair.
PY - 2013/10/24
Y1 - 2013/10/24
N2 - The in vitro activity of a host defense peptidomimetic (HDM-4) was investigated. The compound exhibited an antimicrobial activity profile against a range of Gram-negative bacteria. HDM-4 permeabilized the outer membrane and partly depolarized the inner membrane at its minimal inhibitory concentration (MIC). Moreover, it was demonstrated that HDM-4 was distributed widely in the bacterial cell at lethal concentrations, and that it could bind to DNA. It was confirmed that the multimodal action of HDM-4 resulted in it being less likely to lead to resistance development as compared to single-target antibiotics. HDM-4 exhibited multispecies anti-biofilm activity at sub-MIC levels. Furthermore, HDM-4 modulated the immune response by inducing the release of the chemoattractants interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), and MCP-3 from human peripheral blood mononuclear cells. In addition, the compound suppressed lipopolysaccharide-mediated inflammation by reducing the release of the pro-inflammatory cytokines IL-6 and tumor necrosis factor-α.
AB - The in vitro activity of a host defense peptidomimetic (HDM-4) was investigated. The compound exhibited an antimicrobial activity profile against a range of Gram-negative bacteria. HDM-4 permeabilized the outer membrane and partly depolarized the inner membrane at its minimal inhibitory concentration (MIC). Moreover, it was demonstrated that HDM-4 was distributed widely in the bacterial cell at lethal concentrations, and that it could bind to DNA. It was confirmed that the multimodal action of HDM-4 resulted in it being less likely to lead to resistance development as compared to single-target antibiotics. HDM-4 exhibited multispecies anti-biofilm activity at sub-MIC levels. Furthermore, HDM-4 modulated the immune response by inducing the release of the chemoattractants interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), and MCP-3 from human peripheral blood mononuclear cells. In addition, the compound suppressed lipopolysaccharide-mediated inflammation by reducing the release of the pro-inflammatory cytokines IL-6 and tumor necrosis factor-α.
UR - http://www.scopus.com/inward/record.url?scp=84886797920&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2013.09.007
DO - 10.1016/j.chembiol.2013.09.007
M3 - Article
C2 - 24120333
AN - SCOPUS:84886797920
SN - 1074-5521
VL - 20
SP - 1286
EP - 1295
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 10
ER -