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

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• 作者：Dr. Wenyi Li ; Prof. Neil M. O'Brien-Simpson ; Dr. Shenggen Yao ; Dr. Julien Tailhades ; Prof. Eric C. Reynolds ; Dr. Raymond M. Dawson ; Prof. Laszlo Otvos Jr. ; Dr. Mohammed Akhter Hossain ; Prof. Frances Separovic and Prof. John D. Wade
• 刊名：Chemistry - A European Journal
• 出版年：2017
• 出版时间：January 5, 2017
• 年：2017
• 卷：23
• 期：2
• 页码：390-396
• 全文大小：902K
• ISSN：1521-3765

文摘

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 μan class="smallCaps">man>. A second series of tetrameric analogues with C-terminal hydrazide modification was prepared by using alternative conjugation linkers including trans-1,4-dibromo-2-butene, α,α’-dibromo-p-xylene, or 6-bismaleimidohexane to determine the effect of length on activity. Each displayed potent and broadened activity against Gram-negative nosocomial pathogens, particularly the butene-linked tetrameric hydrazide. Remarkably, the greatest MIC activity is against P. aeruginosa (0.77 μan class="smallCaps">man>/8 μg mL⁻¹) where the monomer is inactive. None of these peptides showed any cytotoxicity to mammalian cells up to 25 times the MIC. A diffusion NMR study of the tetrameric hydrazides showed that the more active antibacterial analogues were those with a more compact structure having smaller hydrodynamic radii. The results show that C-terminal PrAMP hydrazidation together with its rational tetramerization is an effective means for increasing both diversity and potency of PrAMP action.