Journal Article

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

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

2019

Overview

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-NH2 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-NH2 and Lau-RRIWRR-NH2, 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Amino acids / Anti-Infective Agents - chemistry / Anti-Infective Agents - pharmacology / Anti-Infective Agents - toxicity / Antibacterial agents / Antibiotics / Antimicrobial activity / Antimicrobial agents / Antimicrobial Cationic Peptides - chemistry / Antimicrobial Cationic Peptides - pharmacology / Antimicrobial Cationic Peptides - toxicity / Arginine - chemistry / Bacteria / Biology and Life Sciences / Cations / Cell membranes / Cell surface / Communicable diseases / Cytotoxicity / Daptomycin / Datasets / Dosage and administration / Drug Design / Drug discovery / Drug resistance / Drug Resistance, Microbial / Drug Resistance, Multiple / Fatty acids / Gram-positive bacteria / Gram-Positive Bacteria - drug effects / Hemolysis / Hemolysis - drug effects / Humans / In Vitro Techniques / Infectious diseases / Lead compounds / Life sciences / Lipopeptides / Liposomes / Medicine / Medicine and Health Sciences / Membranes / Methicillin / Microbial drug resistance / Microbial Sensitivity Tests / Microorganisms / Minimum inhibitory concentration / Molecular dynamics / Multidrug resistance / Novels / Oligopeptides - chemistry / Oligopeptides - pharmacology / Pathogenic microorganisms / Peptide Library / Peptides / Research and Analysis Methods / Selectivity / Staphylococcus aureus - drug effects / Staphylococcus aureus - ultrastructure / Staphylococcus infections / Surface plasmon resonance / Viability