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Bioorg Med Chem. 2017 Aug 15;25(16):4245-4252. doi: 10.1016/j.bmc.2017.04.040. Epub 2017 Apr 29.

Effect of replacing main-chain ureas with thiourea and guanidinium surrogates on the bactericidal activity of membrane active oligourea foldamers.

Author information

1
Univ. Bordeaux, CBMN, UMR 5248, Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, 33607 Pessac, France; CNRS, CBMN, UMR 5248, F-33600 Pessac, France.
2
HistoPathologie et Modèles Animaux/Pathogénie des Toxi-Infections Bactériennes, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris, France.
3
HistoPathologie et Modèles Animaux/Pathogénie des Toxi-Infections Bactériennes, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris, France. Electronic address: pierre.goossens@pasteur.fr.
4
Univ. Bordeaux, CBMN, UMR 5248, Institut Européen de Chimie et Biologie, 2 rue Robert Escarpit, 33607 Pessac, France; CNRS, CBMN, UMR 5248, F-33600 Pessac, France. Electronic address: g.guichard@iecb.u-bordeaux.fr.

Abstract

Membrane-active foldamers have recently emerged as potential mimics of antimicrobial peptides (AMPs). Amphiphilic cationic helical N,N'-linked oligoureas are one such class of AMP mimics with activities in vitro against a broad range of bacteria including Bacillus anthracis, a Gram-positive sporulating bacillus and causing agent of anthrax. Here we have used site-selective chemical modifications of the oligourea backbone to gain additional insight into the relationship between structure and function and modulate anthracidal activity. A series of analogues in which urea linkages at selected positions are replaced by thiourea and guanidium surrogates have been prepared on solid support and tested against different bacterial forms of B. anthracis (germinated spores and encapsulated bacilli). Urea→thiourea and urea→guanidinium replacements close to the negative end of the helix dipole led to analogues with increased potency and selectivity for B. anthracis versus mammalian cells.

KEYWORDS:

Anthracidal activity; Antimicrobial peptide mimics; Foldamers; Hybrid oligoureas; Structure-activity relationship

PMID:
28687228
DOI:
10.1016/j.bmc.2017.04.040
[Indexed for MEDLINE]

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