Mimicry of Antimicrobial Host-Defense Peptides by Random Copolymers

Brendan P. Mowery,† Sarah E. Lee,† Denis A. Kissounko,† Raquel F. Epand,§ Richard M. Epand,§ Bernard Weisblum,‡ Shannon S. Stahl,*† and Samuel H. Gellman*†;
Department of Chemistry and Department of Pharmacology, University of Wisconsin, Madison, Wisconsin 53706, and Department of Biochemistry and Biomedical Sciences, McMaster University Health Sciences Centre, Hamilton, Ontario L8N 3Z5, Canada
J. Am. Chem. Soc., 2007, 129 (50), pp 15474–15476
DOI: 10.1021/ja077288d
Publication Date (Web): November 23, 2007
Copyright © 2007 American Chemical Society

Abstract

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Efforts to generate antibacterial agents via mimicry of host-defense peptides have focused on discrete oligomers that can adopt a regular globally amphiphilic conformation in the presence of bacterial cell membranes and ultimately disrupt those membranes. Although considerable success has been achieved with this approach, application of the resulting molecules is hampered by the high cost associated with stepwise oligomer synthesis. We show that random poly-β-peptide copolymers, prepared by ring-opening polymerization of β-lactams, can be tuned to display good activity against a panel of four bacteria along with low lytic activity toward human red blood cells. These findings support a nonclassical design hypothesis for antibacterial agents.

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History

  • Published In Issue December 19, 2007
  • Received September 20, 2007

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