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Eur J Med Chem. 2016 Jan 27;108:354-363. doi: 10.1016/j.ejmech.2015.11.032. Epub 2015 Nov 30.

Identification of novel cyclic lipopeptides from a positional scanning combinatorial library with enhanced antibacterial and antibiofilm activities.

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Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie 34987-2352, FLA, USA.
Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, 4202 East Fowler Avenue, ISA2015, Tampa 33620-5150, FLA, USA.
Department of Microbiology and Immunology, Centre for Microbial Diseases and Immunity Research, 232-2259 Lower Mall Research Station, University of British Columbia, Vancouver V6T 1Z4, BC, Canada.
Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FLA, USA.
Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie 34987-2352, FLA, USA. Electronic address:


Treating bacterial infections can be difficult due to innate or acquired resistance mechanisms, and the formation of biofilms. Cyclic lipopeptides derived from fusaricidin/LI-F natural products represent particularly attractive candidates for the development of new antibacterial and antibiofilm agents, with the potential to meet the challenge of bacterial resistance to antibiotics. A positional-scanning combinatorial approach was used to identify the amino acid residues responsible for driving antibacterial activity, and increase the potency of these cyclic lipopeptides. Screening against the antibiotic resistant ESKAPE pathogens revealed the importance of hydrophobic as well as positively charged amino acid residues for activity of this class of peptides. The improvement in potency was especially evident against bacterial biofilms, since the lead cyclic lipopeptide showed promising in vitro and in vivo anti-biofilm activity at the concentration far below its respective MICs. Importantly, structural changes resulting in a more hydrophobic and positively charged analog did not lead to an increase in toxicity toward human cells.


Biofilm; Combinatorial library; Cyclic lipopeptides; Porcine model; Resistance; Toxicity

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