Covalent dimer species of β-defensin Defr1 display potent antimicrobial activity against multidrug-resistant bacterial pathogens

被引:26
|
作者
Taylor, Karen
McCullough, Bryan
Clarke, David J.
Langley, Ross J.
Pechenick, Tali
Hill, Adrian
Campopiano, Dominic J.
Barr, Perdita E.
Dorin, Julia R. [1 ]
Govan, John R. W.
机构
[1] Western Gen Hosp, Med Res Council Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland
[2] Univ Edinburgh, Sch Chem, Edinburgh EH9 3JJ, Midlothian, Scotland
[3] Univ Edinburgh, Sch Med, Edinburgh EH16 4SB, Midlothian, Scotland
基金
英国工程与自然科学研究理事会; 英国医学研究理事会;
关键词
D O I
10.1128/AAC.01531-06
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Beta defensins comprise a family of cationic, cysteine-rich antimicrobial peptides, predominantly expressed at epithelial surfaces. Previously we identified a unique five-cysteine defensin-related peptide (Defr1) that, when synthesized, is a mixture of dimeric isoforms and exhibits potent antimicrobial activity against Escherichia coli and Pseudomonas aeruginosa. Here we report that Defr1 displays antimicrobial activity against an extended panel of multidrug-resistant nosocomial pathogens for which antimicrobial treatment is limited or nonexistent. Defrl fractions were collected by high-pressure liquid chromatography and analyzed by gel electrophoresis and mass spectrometry. Antimicrobial activity was initially investigated with the type strain Pseudomonas aeruginosa PAO1. All fractions tested displayed equivalent, potent antimicrobial activity levels comparable with that of the unfractionated Defrl. However, use of an oxidized, monomeric six-cysteine analogue (Defr1 Y5C, or of reduced Defr1, gave diminished antimicrobial activity. These results suggest that the covalent dimer structure of Defrl is crucial to antimicrobial activity; this hypothesis was confirmed by investigation of a synthetic one-cysteine variant (Defr1-1cys). This gave an activity profile similar to that of synthetic Defrl but only in an oxidized, dimeric form. Thus, we have shown that covalent, dimeric molecules based on the Defr1 beta-defensin sequence demonstrate antimicrobial activity even in the absence of the canonical cysteine motif.
引用
收藏
页码:1719 / 1724
页数:6
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