Solid-phase synthesis and anti-bacterial evaluation of cyclic lipopeptide antibiotics

环状脂肽类抗生素的固相合成及抗菌评价

• 批准号: EP/D041015/1
• 负责人: John Malkinson
• 金额: $ 15.93万
• 依托单位: University 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%2FD041015%2F1
• 关键词: Solid; phase; synthesis; anti; bacterial

SummaryOne of the principal threats to human health is infection by micro-organisms such as bacteria. Drug treatment is the first line of attack in order to kill the bacteria that are responsible for causing the infection. Drugs have been developed that work as a result of the differences between bacterial cells and human cells. By exploiting these differences, we can kill the bacterial cells and treat the infection without causing damage to the person that is infected. Unfortunately, there are a limited number of ways that we can target the differences between bacteria and humans and, so, there is a limit to the number of different types of antibiotic drugs that we can make. There is a lot of current research into new drugs that can kill bacterial cells in different ways.Over-use of antibiotics can cause bacteria to become resistant. Bacteria divide rapidly and the new bacterial cells that are produced are never exactly the same at the cells that they were produced from. Each time a bacterial cell copies itself, the copy is not perfect : there will be something very slightly different about the new cell. Sometimes these small differences that occur when the bacteria divide mean that they are no longer killed by an antibiotic: the small difference affects the part of the bacterial cell where the antibiotic works. So if someone with an infection is treated with an antibiotic, the antibiotic will kill nearly all of the bacteria, but there may be some left over that are not affected by the antibiotic. These survivors can then begin to divide and divide until there is a new infection, but this time, the bacteria are resistant to the antibiotic. Most of the antibiotics that we use have been around for a very long time, so there are some bacteria that are resistant to nearly all of them. The most well known of the resistant bacteria that is responsible for many deaths each year from infections acquired in hospitals is MRSA.One of the best sources of well-known and new drugs is nature. Many antibiotic drugs were first isolated from fungi (e.g. penicillin) or from other bacteria. Bacteria often produce antibiotics as a self-defence mechanism to kill other bacteria. One such new antibiotic that has recently been licensed for use is daptomycin. Daptomycin kills bacteria in a new way; it interferes will the bacterial cell wall causing the contents of the bacteria to leak out. Since daptomycin works in a new way, it can kill bacteria that are resistant to all other antibiotics. Finding antibiotics that work in new ways is very important as it allows us to treat resistant infections that may otherwise be life-threatening.Daptomycin is made up from a ring of amino acids (the building blocks that make up proteins) to which a small fat is attached. Rather than extract and produce daptomycin from bacteria, this research project will develop a method to produce it synthetically. We will build-up the structure attached to small plastic beads using these amino acids in a stepwise manner. Once the molecule is finished, it will be removed from the bead and purified. We will use the same method to make small changes to the structure of the antibiotic to see which parts of the drug molecule are important for its activity as an antibiotic. We will also use the methods developed to synthesise other, similar antibiotics that are produced by other bacteria, to see if they have similar activity. There are many different kinds of antibiotics very similar to daptomycin that may be very useful drugs, but they have yet to be studied in any detail. All of the antibiotics that we produce will be tested for their ability to kill bacteria, including MRSA.This research project will give us a new method of making these antibiotics and will help us to understand how they work. It will also allow us to develop new antibiotics that may eventually be useful as drugs to treat life-threatening infections in patients.

对人类健康的主要威胁之一是微生物如细菌的感染。药物治疗是第一道攻击线，以杀死导致感染的细菌。由于细菌细胞和人类细胞之间的差异，已经开发出了药物。通过利用这些差异，我们可以杀死细菌细胞并治疗感染，而不会对感染者造成伤害。不幸的是，我们可以针对细菌和人类之间的差异的方法有限，因此，我们可以制造的不同类型的抗生素药物的数量有限。目前有很多新药的研究可以通过不同的方式杀死细菌细胞。过度使用抗生素会导致细菌产生耐药性。细菌快速分裂，产生的新细菌细胞与产生它们的细胞永远不会完全相同。每次细菌细胞自我复制时，复制都不是完美的：新细胞会有一些非常轻微的不同。有时，细菌分裂时出现的这些微小差异意味着它们不再被抗生素杀死：微小的差异会影响抗生素发挥作用的细菌细胞部分。因此，如果感染的人用抗生素治疗，抗生素会杀死几乎所有的细菌，但可能会留下一些不受抗生素影响的细菌。然后这些幸存者可以开始分裂和分裂，直到有一个新的感染，但这一次，细菌对抗生素有抗药性。我们使用的大多数抗生素已经存在了很长一段时间，所以有一些细菌对几乎所有的抗生素都有抗药性。耐甲氧西林金黄色葡萄球菌（MRSA）是最著名的耐药细菌，每年都有许多人死于医院感染。许多抗生素药物最初是从真菌（如青霉素）或其他细菌中分离出来的。细菌通常会产生抗生素作为杀死其他细菌的自卫机制。达托霉素就是最近获准使用的一种新抗生素。达托霉素以一种新的方式杀死细菌;它会干扰细菌细胞壁，导致细菌内容物泄漏。由于达托霉素以一种新的方式起作用，它可以杀死对所有其他抗生素具有耐药性的细菌。找到以新方式发挥作用的抗生素非常重要，因为它使我们能够治疗可能危及生命的耐药性感染。达托霉素是由一个氨基酸环（构成蛋白质的结构单元）组成，小脂肪附着在其上。该研究项目将开发一种合成生产达托霉素的方法，而不是从细菌中提取和生产达托霉素。我们将逐步使用这些氨基酸建立附着在小塑料珠上的结构。一旦分子完成，它将从珠中取出并纯化。我们将使用相同的方法对抗生素的结构进行微小的改变，以了解药物分子的哪些部分对其作为抗生素的活性很重要。我们还将使用开发的方法来合成其他细菌产生的其他类似抗生素，看看它们是否具有类似的活性。有许多不同种类的抗生素与达托霉素非常相似，它们可能是非常有用的药物，但它们尚未被详细研究。我们生产的所有抗生素都将被测试其杀死细菌的能力，包括MRSA。这项研究项目将为我们提供一种制造这些抗生素的新方法，并将帮助我们了解它们是如何工作的。它还将使我们能够开发新的抗生素，这些抗生素最终可能用作治疗危及患者生命的感染的药物。