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

• DOI: 10.1016/j.ejmech.2015.11.032
• Publication Date: 2015-11-30T18:04:47Z
• Authors: Nina Bionda; Renee M. Fleeman; César de la Fuent...; Maria C. Rodriguez; Fany Reffuveille; Lindsey N. Shaw; Irena Pastar; Stephen C. Davis; Robert E.W. Hancock; Predrag Cudic
• Keywords: Acinetobacter baumannii; 0301 basic medicine; Staphylococcus aureus; Cell Survival; 610; Microbial Sensitivity Tests; Microbiology; Peptides, Cyclic; Cell Line; Dose-Response Relationship; Cell and Developmental Biology; Lipopeptides; Structure-Activity Relationship; 03 medical and health sciences; Peptide Library; Combinatorial Chemistry Techniques; Humans; Combinatorial library Cyclic lipopeptides Biofilm Porcine model Resistance Toxicity; Biology; Cyclic; 0303 health sciences; Dose-Response Relationship, Drug; Molecular Structure; Cell Biology; 540; [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology; 620; Anti-Bacterial Agents; 3. Good health; Biofilms; Pseudomonas aeruginosa; Drug; [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology; Peptides

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.