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Developing anti-plasmid compounds to combat drug resistant infections

开发抗质粒化合物来对抗耐药感染

基本信息

批准号：
MR/V009885/1
负责人：
Michelle Buckner
金额：
$ 70.25万
依托单位：
University of Birmingham
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FV009885%2F1
关键词：
Developing anti plasmid compounds combat

项目摘要

Antibiotics underpin modern medicine, they are used to treat and prevent bacterial infections. Antibiotics are extremely important for people with reduced immune function such as the young, elderly, transplant recipients, HIV/AIDs and other viral infections, surgery and cancer patients. However, resistance to antibiotics is rapidly growing, reducing their effectiveness. Developing new antimicrobials has proven difficult. With few new classes of antibiotics introduced to the clinic since the 1980s. Therefore, preventing the spread of antibiotic resistance and finding ways to make bacteria susceptible to existing antibiotics are attractive strategies to maintain antibiotic effectiveness. One reason for the antibiotic resistance crisis is that bacteria easily share genetic information. They can do this through different ways, including "plasmid transmission." Plasmids are pieces of genetic material that can move between bacterial cells. These plasmids often carry the genes needed to mediate their movement, or transmission, into new bacteria. They frequently carry resistance multiple different types of antibiotics; thus, bacteria can become resistant to multiple antibiotics in one step. This sharing of resistance plasmids frequently occurs in locations such as the gastrointestinal tract, and occurs on a global scale. For example, antibiotic resistance plasmids are often acquired by people travelling to different parts of the world, and can then be shared with family members upon return. Importantly, these antibiotic resistance genes often convey resistance to some of our last-line-of-defence antibiotics, which are essential in treating difficult infections. Globally, huge quantities of antibiotics are used and misused in humans and animals. This exposes the normal bacteria within the gastrointestinal tract to antibiotics, and this encourages the spread of antibiotic resistance. This makes the gut a key location for these antibiotic resistance plasmids. We are only beginning to understand these real-world antibiotic resistance plasmids in the gut, beyond their DNA sequences and high prevalence. My research aims to develop drugs that will remove antibiotic resistance plasmids from bacterial populations, such as the gut. This would make bacteria treatable using our existing antibiotics, and help to keep them sensitive to new antibiotics in the future. To accomplish this, I have already constructed a system that allows us to "watch" the movement of antibiotic resistance plasmids in bacteria using fluorescence. This system enabled us to look for already-approved drugs and plant-based compounds that reduce the prevalence of antibiotic resistance plasmids. From this we have identified drugs and compounds which effectively reduce plasmid prevalence in bacteria. During this project we will determine which types of antibiotic resistance plasmids each drug/compound works on and how they work to reduce plasmid prevalence in bacteria. Understanding how they work is an important step in bringing new therapies to market. Drugs/compounds will be tested in models of gastrointestinal infection and inflammation. Using these models, we will measure plasmid movement and prevalence in the gut, and determine if the drugs/compounds are able to reduce antibiotic resistance. My research is based upon finding new ways to remove antibiotic resistance from bacteria found in the mammalian gastrointestinal tract. This could be applied to humans and animals to reduce the incidence of drug resistant bacterial infections.

抗生素是现代医学的基础，它们被用来治疗和预防细菌感染。抗生素对于免疫功能下降的人非常重要，如年轻人，老年人，移植受体，HIV/AIDS和其他病毒感染，手术和癌症患者。然而，对抗生素的耐药性正在迅速增长，降低了它们的有效性。事实证明，开发新的抗菌剂是困难的。自20世纪80年代以来，很少有新的抗生素被引入临床。因此，防止抗生素耐药性的传播和找到使细菌对现有抗生素敏感的方法是保持抗生素有效性的有吸引力的策略。抗生素耐药性危机的一个原因是细菌很容易分享遗传信息。他们可以通过不同的方式做到这一点，包括“质粒传播”。“质体是可以在细菌细胞之间移动的遗传物质。这些质粒通常携带介导它们移动或传播到新细菌中所需的基因。它们经常对多种不同类型的抗生素产生耐药性;因此，细菌可以一步对多种抗生素产生耐药性。这种耐药质粒的共享经常发生在胃肠道等部位，并在全球范围内发生。例如，抗生素耐药性质粒通常由前往世界不同地区的人获得，然后可以在返回时与家庭成员分享。重要的是，这些抗生素耐药基因通常会对我们的一些最后一道防线抗生素产生耐药性，这些抗生素在治疗困难的感染中至关重要。在全球范围内，大量的抗生素在人类和动物中被使用和滥用。这使胃肠道内的正常细菌暴露于抗生素，这鼓励了抗生素耐药性的传播。这使得肠道成为这些抗生素耐药性质粒的关键位置。我们才刚刚开始了解肠道中这些真实世界的抗生素耐药性质粒，超越了它们的DNA序列和高流行率。我的研究旨在开发药物，从细菌种群（如肠道）中去除抗生素耐药性质粒。这将使细菌可以使用我们现有的抗生素治疗，并有助于保持它们对未来新抗生素的敏感性。为了实现这一点，我已经构建了一个系统，允许我们使用荧光“观察”细菌中抗生素耐药性质粒的运动。该系统使我们能够寻找已经批准的药物和植物化合物，以减少抗生素耐药性质粒的流行。由此，我们已经确定了有效减少细菌中质粒流行的药物和化合物。在这个项目中，我们将确定每种药物/化合物作用于哪种类型的抗生素耐药性质粒，以及它们如何减少细菌中的质粒流行。了解它们的工作原理是将新疗法推向市场的重要一步。将在胃肠道感染和炎症模型中测试药物/化合物。使用这些模型，我们将测量肠道中的质粒运动和流行率，并确定药物/化合物是否能够降低抗生素耐药性。我的研究是基于寻找新的方法来消除哺乳动物胃肠道细菌的抗生素耐药性。这可以应用于人类和动物，以减少耐药细菌感染的发生率。