Developing anti-plasmid compounds to combat drug resistant 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。抗生素对免疫功能低下的人群极为重要，如年轻人、老年人、移植受者、艾滋病毒/艾滋病和其他病毒感染者、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。开发新的抗微生物药物已被证明是困难的。自从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共享遗传信息。它们可以通过不同的方式做到这一点，包括“质粒传播”。质粒是一种可以在细菌细胞间移动的遗传物质。这些质粒通常携带介导其运动或传播到新细菌所需的基因。它们经常对多种不同类型的抗生素产生耐药性；因此，细菌可以在一步中对多种抗生素产生耐药性。这种耐药性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是由到世界不同地区旅行的人获得的，然后可以在返回时与家庭成员共享。重要的是，这些抗生素耐药基因通常对我们的一些最后防线抗生素产生耐药性，这些抗生素对治疗难治性感染至关重要。在全球范围内，人类和动物使用和滥用了大量抗生素。这会使胃肠道内的正常细菌暴露于抗生素之下，从而促进抗生素耐药性的传播。这使得肠道成为这些抗生素抗性质粒的关键位置。除了它们的DNA序列和高流行率，我们才刚刚开始了解肠道中这些真实世界的抗生素抗性质粒。我的研究目标是开发一种药物，可以从细菌种群（如肠道）中去除抗生素抗性质粒。这将使细菌可以用我们现有的抗生素治疗，并有助于保持它们对未来的新抗生素的敏感性。为了实现这一目标，我已经构建了一个系统，使我们能够使用荧光“观察”细菌中抗生素抗性质粒的运动。该系统使我们能够寻找已经批准的药物和植物基化合物，以减少抗生素抗性质粒的流行。由此，我们已经确定了有效降低细菌中质粒流行率的药物和化合物。在这个项目中，我们将确定每种药物/化合物对哪种类型的抗生素抗性质粒起作用，以及它们如何减少质粒在细菌中的流行。了解它们的工作原理是将新疗法推向市场的重要一步。药物/化合物将在胃肠道感染和炎症模型中进行测试。利用这些模型，我们将测量质粒在肠道中的运动和流行情况，并确定药物/化合物是否能够减少抗生素耐药性。我的研究是基于寻找新的方法来消除哺乳动物胃肠道中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。

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.