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

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.

• Authors: 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
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 34 Issue 1 Pg. 192-207 (01 2020) ISSN: 1530-6860 [Electronic] United States
• PMID: 31914681 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Federation of American Societies for Experimental Biology.

Chemical References

• Anti-Bacterial Agents
• Lipopolysaccharides
• Peptides

Topics

• Animals
• Anti-Bacterial Agents (chemical synthesis, pharmacology)
• Bacteria (drug effects)
• Drug Resistance, Multiple, Bacterial
• Female
• Immunocompromised Host
• Lipopolysaccharides
• Lung (microbiology)
• Mice
• Mice, Inbred BALB C
• Microbial Sensitivity Tests
• Peptides (chemical synthesis, pharmacology)
• Pneumonia, Bacterial (drug therapy, microbiology)
• Pseudomonas Infections (drug therapy, microbiology)
• Pseudomonas aeruginosa
• RAW 264.7 Cells
• Toxicity Tests