Binaphthyl-based dicationic peptoids with therapeutic potential



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Bremner, J. B., Keller, P. A., Pyne, S. G., Boyle, T., Brkic, Z., David, D., Garas, A., Morgan, J., Robertson, M., Somphol, K., Miller, M., Howe, A. S., Ambrose, P., Bhavnani, S., Fritsche, T. R., Biedenbach, D. J., Jones, R. N., Buckheit Jr, R. W., Watson, K., Baylis, D., Coates, J., Deadman, J., Jeevarajah, D., McCracken, A. & Rhodes, D. (2010). Binaphthyl-based dicationic peptoids with therapeutic potential. Angewandte Chemie (International Edition), 49 (3), 537-540.


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[4] of such resistance emerged in 1988, and has subsequently widened amongst the enterococci[5] and staphylococci, including methicillin-resistant Staphylococcus aureus (MRSA);[1, 2] cross-resistance to linezolid[6] is also a concern. Some recent chemical strategies for overcoming this resistance[7] have centered on other high molecular weight cyclic peptides,[8–10] elegantly crafted vancomycin[11] or vancomycin aglycone[12, 13] analogues, potent dual-action vancomycin/ b-lactam hybrid antibiotics,[14] 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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