Multimerization of a Proline-Rich Antimicrobial Peptide, Chex-Arg20, Alters Its Mechanism of Interaction with the Escherichia coli Membrane

Wenyi Li; Neil M O'Brien-Simpson; Julien Tailhades; Namfon Pantarat; Raymond M Dawson; Laszlo Otvos; Eric C Reynolds; Frances Separovic; Mohammed Akhter Hossain; John D Wade

Journal article

Multimerization of a Proline-Rich Antimicrobial Peptide, Chex-Arg20, Alters Its Mechanism of Interaction with the Escherichia coli Membrane

Wenyi Li, Neil M O'Brien-Simpson, Julien Tailhades, Namfon Pantarat, Raymond M Dawson, Laszlo Otvos, Eric C Reynolds, Frances Separovic, Mohammed Akhter Hossain, John D Wade

CHEMISTRY & BIOLOGY | CELL PRESS | Published : 2015

DOI: 10.1016/j.chembiol.2015.08.011

Abstract

A3-APO, a de novo designed branched dimeric proline-rich antimicrobial peptide (PrAMP), is highly effective against a variety of in vivo bacterial infections. We undertook a selective examination of the mechanism for the Gram-negative Escherichia coli bacterial membrane interaction of the monomer (Chex-Arg20), dimer (A3-APO), and tetramer (A3-APO disulfide-linked dimer). All three synthetic peptides were effective at killing E. coli. However, the tetramer was 30-fold more membrane disruptive than the dimer while the monomer showed no membrane activity. Using flow cytometry and high-resolution fluorescent microscopy, it was observed that dimerization and tetramerization of the Chex-Arg20 mono..

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University of Melbourne Researchers

Eric Reynolds Author Melbourne Dental School

Frances Separovic Author Chemistry

Neil O'Brien-Simpson Author Melbourne Dental School

Akhter Hossain Author Florey Department of Neuroscience and Mental Health

Wenyi Li Author Melbourne Dental School

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Grants

Awarded by ARC Discovery Project

Awarded by NHMRC Project

Funding Acknowledgements

Super-resolution imaging was performed at the Materials Characterization and Fabrication Platform (MCFP) at the University of Melbourne. We thank Shu Lam and Greg Qiao (Chemical and Biomolecular Engineering, University of Melbourne) for assistance with application of their high-resolution fluorescent microscopy technique to our studies. We gratefully acknowledge support of the studies undertaken in the authors' laboratory by an ARC Discovery Project grant (DP150103522) to J.D.W. and M.A.H., and NHMRC Project grants (APP1029878) to N.M.O'B.S. and (APP1008106) to E.C.R. and N.M.O'B.S. J.D.W. is an NHMRC (Australia) Principal Research Fellow. W.L. is the recipient of an MIRS PhD award. Research at the FNI was also supported by the Victorian Government's Operational Infrastructure Support Program.