Journal article

C-Terminal Modification and Multimerization Increase the Efficacy of a Proline-Rich Antimicrobial Peptide

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

Chemistry - A European Journal | WILEY-V C H VERLAG GMBH | Published : 2017

Abstract

Two series of branched tetramers of the proline-rich antimicrobial peptide (PrAMP), Chex1-Arg20, were prepared to improve antibacterial selectivity and potency against a panel of Gram-negative nosocomial pathogens including Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa. First, tetramerization was achieved by dithiomaleimide (DTM) conjugation of two C-terminal-cysteine bearing dimers that also incorporated C-terminal peptide chemical modification. DTM-linked tetrameric peptides containing a C-terminal hydrazide moiety on each dimer exhibited highly potent activities in the minimum inhibitory concentration (MIC) range of 0.49-2.33 μm. A second seri..

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Funding Acknowledgements

Ms. Mina Barzegar Amiri Olia (School of Chemistry, University of Melbourne) assisted with photoluminescence measurements. We gratefully acknowledge support of the studies undertaken in the authors' laboratory by ARC Discovery Project grants (DP150103522) to J.D.W. and M.A.H., and (DP140102127) to F.S., 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 and Dr. Albert Shimmins postgraduate writing-up award. Research at the FINMH was also supported by the Victorian Government's Operational Infrastructure Support Program.