Binaphthyl-based dicationic peptoids with therapeutic potential
While the cationic glycopeptide vancomycin has long been regarded as the gold standard for the treatment of recalcitrant Gram-positive bacterial infection, this position has been compromised by the emergence of resistant strains.[1–3] The first report of such resistance emerged in 1988, and has subsequently widened amongst the enterococci and staphylococci, including methicillin-resistant Staphylococcus aureus (MRSA);[1, 2] cross-resistance to linezolid is also a concern. Some recent chemical strategies for overcoming this resistance have centered on other high molecular weight cyclic peptides,[8–10] elegantly crafted vancomycin or vancomycin aglycone[12, 13] analogues, potent dual-action vancomycin/ b-lactam hybrid antibiotics, or large vancomycin dimers.[15, 16] An alternative strategy is to design smaller, simpler cationic peptoids with some related design features to vancomycin which could still interact with the altered peptide-glycan cell-wall moiety in both vancomycin-resistant[ 3] and -sensitive strains and thus broaden the antibacterial spectrum. Svendsen et al. designed minimal cationic peptidomimetics, and a pharmacophore has been developed for dipeptides which includes the presence of two cationic charges and two hydrophobic units of steric bulk.[17–19] Subsequently, cationic tripeptide analogues were developed[ 20, 21] that demonstrated good activity against both Gram-positive (including MRSA) and Gram-negative bacteria, but were not evaluated with respect to vancomycinresistant strains.[20, 21]
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