Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital

Novel Cyclic Lipopeptide Antibiotics: Effects of Acyl Chain Length and Position

Research output: Contribution to journalJournal articleResearchpeer-review


  1. Correlation of MET-Receptor Overexpression with MET Gene Amplification and Patient Outcome in Malignant Mesothelioma

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. The collagen receptor uparap in malignant mesothelioma: A potential diagnostic marker and therapeutic target

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Structure-Activity Study of an All-d Antimicrobial Octapeptide D2D

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. 10-year follow-up after standardised treatment for Achilles tendinopathy

    Research output: Contribution to journalJournal articleResearchpeer-review

View graph of relations

Multidrug-resistant bacteria are a global health problem. One of the last-resort antibiotics against Gram-negative bacteria is the cyclic lipopeptide colistin, displaying a flexible linker with a fatty acid moiety. The aim of the present project was to investigate the effect on antimicrobial activity of introducing fatty acid moieties of different lengths and in different positions in a cyclic peptide, S3(B), containing a flexible linker. The lipidated analogues of S3(B) were synthesized by 9-fluorenylmethoxycarbonyl (Fmoc) solid-phase peptide synthesis. Following assembly of the linear peptide by Fmoc solid-phase peptide synthesis, on-resin head-to-tail cyclization and fatty acid acylation were performed. The antimicrobial activity was determined against the ESKAPE pathogens, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli. Furthermore, hemolytic activity was determined against human erythrocytes. A total of 18 cyclic lipopeptides were synthesized and characterized. It was found that introduction of fatty acids in positions next to the flexible linker was more strongly linked to antimicrobial activity. The fatty acid length altered the overall hydrophobicity, which was the driving force for both high antimicrobial and hemolytic activity. Peptides became highly hemolytic when carbon-chain length exceeded 10 (i.e., C10), overlapping with the optimum for antimicrobial activity (i.e., C8-C12). The most promising candidate (C8)5 showed antimicrobial activity corresponding to that of S3(B), but with an improved hemolytic profile. Finally, (C8)5 was further investigated in a time-kill experiment.

Original languageEnglish
JournalInternational Journal of Molecular Sciences
Issue number16
Publication statusPublished - 13 Aug 2020

    Research areas

  • Acylation, Anti-Bacterial Agents/chemical synthesis, Cyclization, Fatty Acids/chemistry, Hemolysis/drug effects, Hydrophobic and Hydrophilic Interactions, Lipopeptides/chemical synthesis, Microbial Sensitivity Tests, Pseudomonas aeruginosa/drug effects

ID: 62341957