Title

Binaphthyl-based dicationic peptoids with therapeutic potential

RIS ID

33606

Publication Details

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.

Abstract

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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Link to publisher version (DOI)

http://dx.doi.org/10.1002/anie.200904392