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.

Molecular Antioxidant Properties and In Vitro Cell Toxicity of the p-Aminobenzoic Acid (PABA) Functionalized Peptide Dendrimers §

“…The general strategy for the synthesis of a series of amphiphilic dendrimers containing on the surface p -aminobenzoic acid residues involves synthesis of the tert -butyloxycarbonyl (Boc)-protected new hydrophobic branching units of the AB 1 B 2 type, where B 1 and B 2 denote alkylamino chains of equal or different length (Scheme 1), followed by coupling them with the N α or N ε atoms of lysine functionalized at C-terminus with benzylethylamine, tryptamine, or dodecylamine moiety (compounds 8–11, Scheme 2) was described in detail recently [21]. After deprotection of amino groups such core molecules are then reacted with suitably protected lysine (Scheme 3).…”

“…Schematic representation for the synthetic pathway of branching units 4 and 5 (described in detail in [21]). Boc: tert -Butyloxycarbonyl.…”

An Update on Antimicrobial Peptides (AMPs) and Their Delivery Strategies for Wound Infections

“…They are a very attractive class of molecules as they exhibit high antimicrobial activity against bacteria, fungi, and viruses [97]. Their high antimicrobial activity is mainly due to their positive charges of the amino acid residues that interact with the negatively charged bacterial cell envelope and lead to bacterial death [92,98]. Moreover, AMPDs were shown to be more resistant to proteolysis and less toxic to both mammalian and erythrocyte cells than AMPs.…”

The Role of Branch Cell Symmetry and Other Critical Nanoscale Design Parameters in the Determination of Dendrimer Encapsulation Properties

“…However, recent work by Haridas et al [31] exhaustively reviewed the area of peptide/protein dendrimers and has clearly revealed significant new interest in this overlooked area of dendrimer science. More specifically, Urbanczyk-Lipkowska [47] have described the synthesis and evaluation of amphiphilic peptide dendrimer as specific antimicrobials effective against drug-resistant bacteria [48]; whereas, Reymond et al [49,50] reports the structure-activity relationships for a library of single component, well-defined peptide dendrimers, which are equivalent to Lipofectamine L2000 as a transfection vector for siRNA. That withstanding, substantial commercial interest in poly(peptide)-type (i.e., PL dendrimers has also been noted based on recent nano-medical clinical successes reported by Starpharma, Ltd., Victoria, Austrualia, (www.starpharma.com); wherein, certain PL dendrimers are being marketed and used as antivirals, microbicides (i.e., VivaGel ® ) and targeted cancer therapies (i.e., DEP ® products).…”