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的总结是细菌等微生物感染。药物治疗是杀死导致感染的细菌的第一道攻击。已经开发出由于细菌细胞和人类细胞之间差异而起作用的药物。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损害感染者。不幸的是，我们可以针对细菌与人类之间的差异有多种方法，因此，我们可以制造的不同类型的抗生素药物的数量有限制。当前对新药物的研究有很多研究可以以不同的方式杀死细菌细胞。抗生素的使用可能会导致细菌抗性。细菌迅速分裂，而生产的新细菌细胞在其产生的细胞中永远不会完全相同。每次细菌细胞本身都复制时，该副本并不完美：新单元格会有一些略有不同的东西。有时，当细菌分裂的这些小差异意味着它们不再被抗生素杀死：小差异会影响抗生素起作用的细菌细胞的一部分。因此，如果患有感染的人用抗生素治疗，抗生素几乎会杀死几乎所有细菌，但可能剩下的不受抗生素影响。然后，这些幸存者可以开始分裂并分裂直到有新的感染，但是这次，细菌对抗生素具有抗性。我们使用的大多数抗生素已经存在很长时间了，因此一些细菌几乎对它们都有抗性。 MRSA是MRSA，最知名的细菌中最著名的抗性细菌是许多死亡。首先将许多抗生素药物从真菌（例如青霉素）或其他细菌中分离出来。细菌通常会产生抗生素作为杀死其他细菌的自卫机制。 daptomycin是最近已获得使用许可的一种新的抗生素。 Daptomycin以新的方式杀死细菌。它会干扰细菌细胞壁，从而导致细菌的含量泄漏。由于Daptomycin以一种新的方式起作用，因此可以杀死对所有其他抗生素具有抗性的细菌。寻找以新方式起作用的抗生素非常重要，因为它使我们能够治疗可能威胁生命的耐药性感染。DACTOMYCIN由氨基酸环（构成蛋白质的构建块）组成附着。该研究项目不是从细菌中提取并产生Daptomycin，而是开发一种合成生产的方法。我们将使用这些氨基酸以逐步方式建立附着在小塑料珠上的结构。分子完成后，将将其从珠子中取出并纯化。我们将使用相同的方法对抗生素的结构进行微小的改变，以查看药物分子的哪些部分对于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的抗生素，以查看它们是否具有相似的活性。与Daptomycin非常相似的抗生素有许多不同的抗生素，可能是非常有用的药物，但尚未对其进行任何详细研究。我们生产的所有抗生素都将通过杀死细菌的能力进行测试，包括MRSA。此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的工作原理。它还将使我们能够开发新的抗生素，这些抗生素最终可能作为治疗患者威胁生命的感染的药物有用。