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

抗生素长期以来一直被用于治疗人类的各种疾病。它们通常是非常有用的药物，因为它们能够杀死致病生物体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。原因是致病的有机体已经对药物产生了耐药性，这很简单地意味着它们已经找到了避免药物毒性作用的方法。这种由耐药细菌（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，用于治疗感染耐药细菌的患者。依靠运气和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：现在我们在诊所里遇到了耐药性问题，必须更快地加以处理。更明智的方法是设计以新颖方式起作用的新药，其中一类可能被开发的化合物是抗菌肽家族。当然，这种方法要求我们充分了解这些抗菌肽的工作原理，不幸的是，情况并非如此。据认为，肽可能以某种方式与细菌的外表面相互作用-最有可能是与引起发烧的分子组成块称为脂多糖。然而，肽究竟如何与这些脂多糖相互作用，尚不清楚。在伦敦国王学院进行的这项研究中，目的是找出抗菌肽的工作原理，特别是研究它们与细菌脂多糖相互作用的本质。这项研究将涉及到使用被称为脂质体的微小气泡状结构或非常薄的材料层，其厚度只有一到两个分子，使用不同的细菌脂多糖制备，以便它们模拟细菌细胞及其表面。然后将使用先进的分析技术组合研究这些细菌结构模拟物，同时观察在抗微生物肽存在下膜结构是如何改变的。从这些调查中获得的知识，希望为其他人设计新的和改进的抗生素形式，用于对抗抗生素耐药细菌感染铺平道路。

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.