Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 108, Issue -, Pages 354-363Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.11.032
Keywords
Combinatorial library; Cyclic lipopeptides; Biofilm; Porcine model; Resistance; Toxicity
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Funding
- NIAID NIH HHS [R21 AI119288, 1R21AI119288-01, AI103715, R21 AI103715] Funding Source: Medline
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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. (C) 2015 Elsevier Masson SAS. All rights reserved.
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