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

PloS One
Federica ArmasMonica Benincasa

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-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 hum...Continue Reading

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Citations

Jan 16, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Damian NeubauerWojciech Kamysz
Oct 3, 2020·International Journal of Molecular Sciences·Damian NeubauerWojciech Kamysz
Dec 24, 2020·International Journal of Molecular Sciences·Taylor Rounds, Suzana K Straus
Apr 4, 2021·International Journal of Molecular Sciences·Damian NeubauerWojciech Kamysz
Jun 7, 2021·Advanced Drug Delivery Reviews·Cheng WangJiang Xia
Jul 17, 2021·Nanomedicine·Eric MühlbergPhilipp Uhl
Aug 8, 2021·International Journal of Molecular Sciences·Federica ArmasMarco Scocchi
Mar 3, 2020·Langmuir : the ACS Journal of Surfaces and Colloids·Federica NovelliAnita Scipioni
Nov 26, 2020·ACS Applied Materials & Interfaces·Seong-Cheol ParkDongwon Lee
Jul 21, 2020·Journal of Medicinal Chemistry·John A KarasTony Velkov
Nov 16, 2021·ACS Chemical Biology·Apurva PanjlaSandeep Verma

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Methods Mentioned

BETA
Dynamic Light Scattering
chip
flow cytometry
FCS
surface plasmon resonance
scanning electron microscopy
dynamic light-scattering

Software Mentioned

CHARMM
GenScript
CD
Arta Peptidion
InStat
BIAevaluation
GraphPad
HIT
FCS Express3
- GUI Membrane Builder

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