Molecular mechanisms of antimicrobial peptides: phase changes induced in endotoxic bacterial lipopolysaccharide.

抗菌肽的分子机制：内毒素细菌脂多糖诱导的相变。

• 批准号: EP/G068569/1
• 负责人: Richard Harvey
• 金额: $ 24.93万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FG068569%2F1
• 关键词: Molecular; mechanisms; antimicrobial; peptides; phase

Antibiotics have long been used for treating a variety of diseases in humans. They are generally very useful as drugs because they are able to kill off the disease-causing organisms without producing harmful side effects in patients. Over recent years, however, many of these drugs have become less effective, and in some cases are now totally useless. The reason for this is that the disease-causing organisms have developed a resistance to the drugs / which means quite simply that they have found ways to avoid the drugs' toxic effects.This alarming rise in infections due to drug-resistant bacteria - like MRSA - has given rise to growing public concern, and has prompted a call for new antibiotics that can be used to treat patients infected with the drug-resistant organisms. To trust to luck and hope for some chance discovery of a new drug (as with Fleming's discovery of penicillin, for example) is clearly not satisfactory: the problem of resistance is with us in the clinics now, and must be dealt with more speedily.A more sensible way forward is to design new drugs that work in novel ways, and one such class of compounds that might be exploited are the family of anti-bacterial peptides. Such an approach, of course, requires that we fully understand how these anti-bacterial peptides work, and unfortunately this is not the case. It is thought that the peptides might somehow interact with the bacterial outer surface - most likely with the fever-causing molecular building-blocks known as lipopolysaccharides. Precisely how the peptides interact with these lipopolysaccharides, however, is not yet established.In the research to be carried out at King's College London, the aim is to find out how anti-bacterial peptides work, looking in particular at the nature of their interaction with the bacterial lipopolysaccharides. The research will involve using microscopic, bubble-like structures known as liposomes or very thin layers of material which are the thickness of only one or two molecules, prepared using different bacterial lipoploysaccharides, so that they mimic bacterial cells and their surfaces. These bacterial structure mimics will then be studied using a combination of advanced analytical techniques, looking also at how the membrane structures are changed in the presence of the anti-microbial peptides. From the knowledge gained in these investigations, it is hoped to pave the way for others to design new and improved forms of antibiotic for use against antibiotic-resistant bacterial infections.

抗生素长期以来一直被用于治疗人类的多种疾病。它们通常作为药物非常有用，因为它们能够杀死致病微生物，而不会对患者产生有害的副作用。然而，近年来，这些药物中的许多已经变得不那么有效，在某些情况下现在完全无用。这是因为致病微生物已经对药物产生了抗药性，也就是说它们已经找到了避免药物毒性作用的方法。由于抗药性细菌（如MRSA）引起的感染的惊人增长引起了公众越来越多的关注，并促使人们呼吁开发新的抗生素，用于治疗感染抗药性微生物的患者。相信运气，希望偶然发现一种新药（例如弗莱明发现青霉素）显然是不令人满意的：耐药性问题现在已经在临床上出现，必须更快地加以解决。更明智的前进道路是设计以新方式发挥作用的新药，抗菌肽家族就是这样一类可能被开发的化合物。当然，这种方法需要我们完全理解这些抗菌肽是如何工作的，不幸的是，情况并非如此。人们认为这些肽可能以某种方式与细菌的外表面相互作用--最有可能的是与引起发烧的分子结构单元--脂多糖相互作用。然而，肽与这些脂多糖的确切相互作用方式尚未确定，在伦敦国王学院进行的研究中，目的是找出抗菌肽如何起作用，特别是它们与细菌脂多糖相互作用的性质。这项研究将涉及使用显微镜下的气泡状结构，称为脂质体或非常薄的材料层，这些材料的厚度只有一个或两个分子，使用不同的细菌脂多糖制备，以便它们模仿细菌细胞及其表面。然后将使用先进的分析技术组合来研究这些细菌结构模拟物，同时还研究在抗菌肽存在下膜结构如何改变。从这些研究中获得的知识，希望为其他人设计新的和改进的抗生素形式以用于对抗耐药性细菌感染铺平道路。

项目成果

Lipid domain formation and non-lamellar structures associated with varied lysylphosphatidylglycerol analogue content in a model Staphylococcal plasma membrane.

脂质结构域的形成和非层状结构与模型葡萄球菌质膜中不同的赖氨酰磷脂酰甘油类似物含量相关。

• DOI: 10.1016/j.bbamem.2021.183571
• 发表时间: 2021
• 期刊: Biochimica et biophysica acta. Biomembranes
• 作者: Rehal R

Comparing the action of HT61 and chlorhexidine on natural and model Staphylococcus aureus membranes.

比较 HT61 和氯己定对天然和模型金黄色葡萄球菌膜的作用。

• DOI: 10.1038/ja.2017.90
• 发表时间: 2017
• 期刊: The Journal of antibiotics
• 作者: Hubbard AT

The influence of mild acidity on lysyl-phosphatidylglycerol biosynthesis and lipid membrane physico-chemical properties in methicillin-resistant Staphylococcus aureus.

弱酸性对耐甲氧西林金黄色葡萄球菌赖氨酰磷脂酰甘油生物合成和脂膜理化性质的影响。

• DOI: 10.1016/j.chemphyslip.2017.06.007
• 发表时间: 2017
• 期刊: Chemistry and physics of lipids
• 影响因子: 3.4
• 作者: Rehal RP

The pH-dependence of lipid-mediated antimicrobial peptide resistance in a model staphylococcal plasma membrane: A two-for-one mechanism of epithelial defence circumvention.

模型葡萄球菌质膜中脂质介导的抗菌肽耐药性的 pH 依赖性：上皮防御规避的二合一机制。

• DOI: 10.1016/j.ejps.2018.11.017
• 发表时间: 2019
• 期刊: official journal of the European Federation for Pharmaceutical Sciences
• 作者: Rehal R

Diffraction studies on natural and model lipid bilayers

天然和模型脂质双层的衍射研究

• DOI: 10.1140/epjst/e2012-01682-3
• 发表时间: 2012
• 期刊: The European Physical Journal Special Topics
• 作者: Sebastiani F