Modified peptides as potential new antibiotics versus multiresistent problem strains

修饰肽作为潜在的新抗生素对抗多重耐药问题菌株

• 批准号: 390523201
• 负责人: Professor Dr. Nisar Peter Malek, since 6/2019
• 金额: --
• 依托单位: Innere Medizin I: Gastroenterologie, Hepatologie, Infektionskrankheiten
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/390523201?language=en
• 关键词: Modified; peptides; potential; new; antibiotics

Antimicrobial peptides are endogenous-, small-, usually cationic peptide antibiotics which represent an essential part of innate immune defense. Different of these peptides have a broad range of antimicrobial but also antifungal and antiviral properties. So far we know more then 800 of these host protective molecules. The best characterized group are human defensins which are characterized by disulfid bridges. According to the order and distribution of these bridges they can be divided in alpha and beta defensins. Defensins are produced by all epithelial cells but also different immune cells. One defensin which is expressed everywhere at the surface is human beta defensin 1 (hBD1). Despite its ubiquitous expression the biological function was unclear for a long time time because of only weak antimicrobial properties under normal standard conditions. Our group could show that antimicrobial activity gets unmasked depending on environmental conditions. This activation by reduction seems to be a general principle of nature as it also applies to other peptides. However, the reduced form of the peptide is not stable towards proteases and can be cleaved by duodenal mucus. After proteolytic cleavage small fragments occur which also have antimicrobial properties. We isolated a fragment which is ative against Grampositive and Gram negative bacteria such as S. aureus and E. coli. To improve binding to the muces we added a fatty acid to this small fragment. The basic idea of this proposal is a combination of natural occuring palimin acid with the new discovered antimicrobial fragment. Surprisingly this combined peptide (of acid and defensin fragment) does not only maintain its antimicrobial function but it becomes much more active and is able to kill different multiresistent strains. Here we aim to further explore the underlining mechanisms and principles by using different layers of investigations.

抗菌肽是内源性的，小的，通常是阳离子的肽抗生素，是先天免疫防御的重要组成部分。不同的这些肽有广泛的抗菌，但也抗真菌和抗病毒特性。到目前为止，我们知道超过800种这样的宿主保护分子。最好的特征组是人类防御，其特征是二硫桥。根据这些桥的顺序和分布，它们可以分为α和β防御。防御素由所有上皮细胞产生，但也由不同的免疫细胞产生。一种在表面到处表达的防御蛋白是人β防御蛋白1 （hBD1）。尽管其普遍表达，但由于在正常标准条件下抗菌性能较弱，长期以来生物学功能不明确。我们的团队可以证明，抗菌活性会根据环境条件而暴露出来。这种还原激活似乎是自然界的一般原理，因为它也适用于其他肽。然而，肽的还原形式对蛋白酶不稳定，并可被十二指肠粘液裂解。在蛋白水解裂解后，产生的小片段也具有抗菌特性。我们分离出一个对革兰氏阳性和革兰氏阴性细菌如金黄色葡萄球菌和大肠杆菌具有阳性反应的片段。为了改善与黏液的结合，我们在这个小片段中添加了脂肪酸。该方案的基本思路是将天然棕榈蛋白酸与新发现的抗菌片段相结合。令人惊讶的是，这种结合肽（酸和防御素片段）不仅保持其抗菌功能，而且变得更加活跃，能够杀死不同的多重耐药菌株。在这里，我们的目的是通过使用不同层次的调查，进一步探讨潜在的机制和原则。