BIOPHYSICAL STUDIES OF MODEL BIO-MEMBRANES & INVESTIGATION OF THE MOLECULAR MECHANISM OF THE ANTI-MYCOTIC DRUG, AMPHOTERICIN

模型生物膜的生物物理学研究

• 批准号: EP/F021291/1
• 负责人: David Barlow
• 金额: $ 18.96万
• 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: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FF021291%2F1
• 关键词: BIOPHYSICAL; STUDIES; MODEL; BIO; MEMBRANES

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.One antibiotic, amphotericin, has, until recently, been very good for treating infections caused by fungi / in combating diseases like thrush, for example. Lately, however, there have been increasing numbers of reports where patients suffering from fungal infections have not responded to treatment with amphotericin. There is a growing concern, therefore, that this problem may soon be as widespread as the troubles caused by MRSA, and so there is a call for new antibiotics that can be used to treat patients infected with the amphotericin-resistant fungi. 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 the same way as the old drug, amphotericin, but which are sufficiently different in their chemistry that the disease-causing fungi are not able to counteract their effects. Such an approach, of course, requires that we fully understand how amphotericin works, and unfortunately this is not the case. We do know that the drug has little effect on the cells in a human because these cells are surrounded by membranes containing cholesterol. We also know that the drug exerts its effects on fungi because their cells do not contain cholesterol, but instead have a related steroid, ergosterol. Quite how this difference between human and fungal cell membranes is important in the working of amphotericin, however, remains unclear.In the research to be carried out at King's College London, the aim is to find out precisely why this difference between cholesterol-containing and ergosterol-containing cell membranes is critical, and why, therefore, amphotericin is so damaging to fungi and not to humans. The research will involve using microscopic, bubble-like structures known as liposomes, prepared using different mixtures of fats, and either cholesterol, ergosterol or some other kind of steroid, so that they mimic fungal or human cells. The structures of the membranes surrounding these liposomes 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 antibiotic, amphotericin. 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 amphotericin-resistant fungal 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，这意味着它们已经找到了避免药物毒性作用的方法。例如，一种抗生素，阿替西霉素，直到最近，对治疗真菌引起的感染非常有效。然而，最近有越来越多的报道，其中患有真菌感染的患者对阿替西霉素治疗没有反应。因此，人们越来越担心这个问题可能很快就会像MRSA引起的麻烦一样普遍，因此需要新的抗生素来治疗感染耐甲氧西林真菌的患者。寄希望于运气，希望能偶然发现一种新药（例如弗莱明发现青霉素）显然不能令人满意：抗药性的问题现在在临床上与我们同在，必须更快地处理。一个更明智的方法是设计出与旧药物--阿替西霉素--作用相同的新药，但它们在化学性质上有很大的不同，致病真菌不能抵消它们的作用。当然，这种方法需要我们充分了解阿替西汀的作用机制，不幸的是，情况并非如此。我们确实知道这种药物对人体细胞的影响很小，因为这些细胞被含有胆固醇的膜所包围。我们还知道，这种药物对真菌产生影响，因为它们的细胞不含胆固醇，而是含有一种相关的类固醇，麦角固醇。然而，人类和真菌细胞膜之间的这种差异在阿氏菌素的作用中有何重要性仍不清楚。伦敦国王学院即将进行的研究的目的是准确地找出为什么含胆固醇和含麦角固醇的细胞膜之间的这种差异是至关重要的，以及为什么阿氏菌素对真菌而不是对人类如此有害。这项研究将涉及使用显微镜下的气泡状结构，即脂质体，由不同的脂肪混合物、胆固醇、麦角固醇或其他某种类固醇制备，以模仿真菌或人类细胞。然后，将使用先进的分析技术的组合来研究这些脂质体周围的膜的结构，同时也研究在抗生素存在下膜结构是如何改变的。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用于对抗耐药性真菌感染铺平道路。

项目成果

Neutron Scattering Studies of the Effects of Formulating Amphotericin B with Cholesteryl Sulfate on the Drug's Interactions with Phospholipid and Phospholipid-Sterol Membranes.

两性霉素 B 与胆固醇硫酸盐配制对药物与磷脂和磷脂甾醇膜相互作用影响的中子散射研究。

• DOI: 10.1021/acs.langmuir.5b01365
• 发表时间: 2015
• 期刊: the ACS journal of surfaces and colloids
• 作者: Foglia F