Bioinspired Amphiphilic Peptide Dendrimers as Specific and Effective Compounds against Drug Resistant Clinical Isolates of E. coli.

Abstract

Evolution-derived natural compounds have been inspirational for design of numerous pharmaceuticals, e.g., penicillins and tetracyclines. Herein, we present a bioinspired strategy to design peptide dendrimers for the effective therapy of E. coli infections where the selection of appropriate amino acids and the mode of their assembly are based on the information gained from research on membranolytic natural antimicrobial peptides (AMP's). On the molecular level two opposite effects were explored: the effect of multiple positive charges necessary for membrane disintegration was equilibrated by the anchoring role of tryptophanes. Indeed, a series of Trp-terminated dendrimers exhibited high potency against clinical isolates of antibiotic resistant ESBL E. coli strains, stability in human plasma along with very low hemo- and genotoxicity. Investigation of the underlying antimicrobial mechanism indicated that the dendrimers studied at minimal inhibitory concentration showed weak permeability toward membranes. Solid-state 2D NMR studies revealed their presence on and inside the model membranes. Therefore, their biological properties might be explained by targeting of extra- or intracellular receptors. Our results point to a new approach to design novel branched antimicrobials with high therapeutic index.

• Authors: Marta Sowińska, Anna Laskowska, Adam Guśpiel, Jolanta Solecka, Marta Bochynska-Czyż, Andrzej W Lipkowski, Katarzyna Trzeciak, Zofia Urbanczyk-Lipkowska
• Journal: Bioconjugate chemistry (Bioconjug Chem) Vol. 29 Issue 11 Pg. 3571-3585 (11 21 2018) ISSN: 1520-4812 [Electronic] United States
• PMID: 30235928 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Dendrimers
• Membrane Proteins
• Peptides

Topics

• Anti-Bacterial Agents (chemistry, pharmacology)
• Cell Line, Tumor
• Cell Membrane Permeability
• Dendrimers (chemistry, pharmacology)
• Drug Resistance, Bacterial (drug effects)
• Escherichia coli (drug effects)
• Hemolysis (drug effects)
• Humans
• Membrane Proteins (chemistry)
• Microbial Sensitivity Tests
• Nuclear Magnetic Resonance, Biomolecular (methods)
• Peptides (chemistry, pharmacology)