Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.
Antimicrob Agents Chemother. 2012 May;56(5):2696-704. doi: 10.1128/AAC.00064-12. Epub 2012 Feb 21.
Biofilms cause up to 80% of infections and are difficult to treat due to their substantial multidrug resistance compared to their planktonic counterparts. Based on the observation that human peptide LL-37 is able to block biofilm formation at concentrations below its MIC, we screened for small peptides with antibiofilm activity and identified novel synthetic cationic peptide 1037 of only 9 amino acids in length. Peptide 1037 had very weak antimicrobial activity, but at 1/30th the MIC the peptide was able to effectively prevent biofilm formation (>50% reduction in cell biomass) by the Gram-negative pathogens Pseudomonas aeruginosa and Burkholderia cenocepacia and Gram-positive Listeria monocytogenes. Using a flow cell system and a widefield fluorescence microscope, 1037 was shown to significantly reduce biofilm formation and lead to cell death in biofilms. Microarray and follow-up studies showed that, in P. aeruginosa, 1037 directly inhibited biofilms by reducing swimming and swarming motilities, stimulating twitching motility, and suppressing the expression of a variety of genes involved in biofilm formation (e.g., PA2204). Comparison of microarray data from cells treated with peptides LL-37 and 1037 enabled the identification of 11 common P. aeruginosa genes that have a role in biofilm formation and are proposed to represent functional targets of these peptides. Peptide 1037 shows promise as a potential therapeutic agent against chronic, recurrent biofilm infections caused by a variety of bacteria.
生物膜可导致高达 80%的感染，并且由于其与浮游生物相比具有实质性的多药耐药性，因此难以治疗。基于观察到人类肽 LL-37 能够在低于其 MIC 的浓度下阻止生物膜形成的现象，我们筛选了具有抗生物膜活性的小肽，并鉴定出一种仅 9 个氨基酸长的新型合成阳离子肽 1037。肽 1037 的抗菌活性非常弱，但在 MIC 的 1/30 时，该肽能够有效阻止革兰氏阴性病原体铜绿假单胞菌和伯克霍尔德菌属假单胞菌和革兰氏阳性李斯特菌的生物膜形成（细胞生物量减少超过 50%）。使用流动池系统和宽场荧光显微镜，显示 1037 可显著减少生物膜形成，并导致生物膜中的细胞死亡。微阵列和后续研究表明，在铜绿假单胞菌中，1037 通过降低游泳和群集运动、刺激抽搐运动以及抑制各种与生物膜形成相关的基因的表达（例如，PA2204）来直接抑制生物膜。用肽 LL-37 和 1037 处理的细胞的微阵列数据的比较使我们能够鉴定出 11 个常见的铜绿假单胞菌基因，这些基因在生物膜形成中具有作用，并被提议作为这些肽的功能靶标。肽 1037 有望成为治疗各种细菌引起的慢性、复发性生物膜感染的潜在治疗剂。
