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An antimicrobial molecule mitigates signs of sepsis in vivo and eradicates infections from lung tissue.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2020-01-10)
Leila Quercini, Jlenia Brunetti, Giulia Riolo, Stefano Bindi, Silvia Scali, Ilaria Lampronti, Elisabetta D'Aversa, Sabine Wronski, Simona Pollini, Mariangela Gentile, Pietro Lupetti, Gian Maria Rossolini, Chiara Falciani, Luisa Bracci, Alessandro Pini
ABSTRACT

The peptide sequence KKIRVRLSA was synthesized in a dimeric structure (SET-M33DIM) and evaluated as a candidate drug for infections due to multidrug-resistant (MDR) Gram-negative pathogens. SET-M33DIM showed significant antibacterial activity against MDR strains of Klebsiella pneumoniae, Acinetobacter baumannii, and Escherichia coli (Minimal Inhibitory Concentration [MICs], 1.5-11 µM), and less activity against Pseudomonas aeruginosa (MICs, 11-22 µM). It showed very low toxicity in vitro, ex vivo, and in vivo; in cytotoxicity tests, its EC50 was as much as 22 times better than that of SET-M33, a peptide with the same amino-acid sequence, but synthesized in tetra-branched form (638 vs 28 µM). In in vivo and ex vivo experiments, SET-M33DIM cleared P. aeruginosa infection, significantly reducing signs of sepsis in animals, and restoring cell viability in lung tissue after bacterial challenge. It also quelled inflammation triggered by LPS and live bacterial cells, inhibiting expression of inflammatory mediators in lung tissue, cultured macrophages, and bronchial cells from a cystic fibrosis patient.

MATERIALS
Product Number
Brand
Product Description

Supelco
Vial, Chromacol, PTFE (non-disposable sleeve), O.D. × H 12 mm × 32 mm, for use with Supelco part numbers 27312, 27313, 27314, 27315, pkg of 40 ea
Sigma-Aldrich
Lipopolysaccharides from Escherichia coli O26:B6, ≥10,000 EU/mg, purified by phenol extraction
Sigma-Aldrich
Boc-Ala-OH, ≥99.0% (TLC)
Sigma-Aldrich
Lipopolysaccharides from Klebsiella pneumoniae, purified by phenol extraction
Sigma-Aldrich
Cyclophosphamide monohydrate, ISOPAC®
Sigma-Aldrich
Calcein, Used for the fluorometric determination of calcium and EDTA titration of calcium in the presence of magnesium.