Design, antimicrobial activity and mechanism of action of Arg-rich ultra-short cationic lipopeptides

Federica Armas, Sabrina Pacor, Elena Ferrari, Filomena Guida, Thelma A. Pertinhez, Antonello A. Romani, Marco Scocchi, Monica Benincasa

Research output: Contribution to journalArticle

Abstract

The increasing emergence of multidrug-resistant microorganisms represents one of the greatest challenges in the clinical management of infectious diseases, and requires the development of novel antimicrobial agents. To this aim, we de novo designed a library of Arg-rich ultra-short cationic antimicrobial lipopeptides (USCLs), based on the Arg-X-Trp-Arg-NH 2 peptide moiety conjugated with a fatty acid, and investigated their antibacterial potential. USCLs exhibited an excellent antimicrobial activity against clinically pathogenic microorganisms, in particular Gram-positive bacteria, including multidrug resistant strains, with MIC values ranging between 1.56 and 6.25 μg/mL. The capability of the two most active molecules, Lau-RIWR-NH 2 and Lau-RRIWRR-NH 2 to interact with the bacterial membranes has been predicted by molecular dynamics and verified on liposomes by surface plasmon resonance. Both compounds inhibited the growth of S. aureus even at sub MIC concentrations and induced cell membranes permeabilization by producing visible cell surface alterations leading to a significant decrease in bacterial viability. Interestingly, no cytotoxic effects were evidenced for these lipopeptides up to 50–100 μg/mL in hemolysis assay, in human epidermal model and HaCaT cells, thus highlighting a good cell selectivity. These results, together with the simple composition of USCLs, make them promising lead compounds as new antimicrobials.

Original languageEnglish
Article numbere0212447
JournalPLoS One
Volume14
Issue number2
DOIs
Publication statusPublished - Feb 1 2019

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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    Armas, F., Pacor, S., Ferrari, E., Guida, F., Pertinhez, T. A., Romani, A. A., Scocchi, M., & Benincasa, M. (2019). Design, antimicrobial activity and mechanism of action of Arg-rich ultra-short cationic lipopeptides. PLoS One, 14(2), [e0212447]. https://doi.org/10.1371/journal.pone.0212447