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

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。一种抗生素，两性霉素，直到最近，在治疗真菌引起的感染/对抗鹅口疮等疾病方面都非常有效。然而，最近有越来越多的报道称，患有真菌感染的患者对两性霉素治疗没有反应。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，人们呼吁开发新的抗生素，用于治疗感染了两性霉素耐药真菌的患者。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。一种更明智的方法是设计一种新药，这种新药的作用原理与旧药两性霉素相同，但它们的化学成分完全不同，导致致病的真菌无法抵消它们的作用。当然，这样的方法要求我们完全了解两性霉素是如何起作用的，不幸的是，事实并非如此。我们知道这种药物对人体细胞几乎没有影响，因为这些细胞被含有胆固醇的膜包围着。我们还知道，这种药物对真菌起作用是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甾醇。然而，人类和真菌细胞膜之间的这种差异在两性霉素的作用中是如何重要的，目前尚不清楚。在伦敦国王学院进行的这项研究中，其目的是精确地找出为什么含胆固醇和含麦角甾醇的细胞膜之间的这种差异是至关重要的，以及为什么两性霉素对真菌而不是对人类具有如此大的破坏性。这项研究将涉及使用被称为脂质体的微小气泡状结构，脂质体由不同的脂肪、胆固醇、麦角甾醇或其他种类的类固醇混合而成，从而模拟真菌或人类细胞。然后将使用先进的分析技术来研究这些脂质体周围的膜结构，同时观察在抗生素两性霉素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，用于对抗两性霉素耐药真菌感染铺平道路。

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.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.