Applying New Tools to Identify Inhibitors of Antimicrobial Resistance Plasmid Transmission or Stability in Gram Negative Bacteria

抗生素和抗菌剂是现代人类和兽医医学的基础。它们通常不仅用于治疗感染，而且还用于手术前，对于免疫功能低下的脆弱患者，包括年轻人、老年人、移植患者、癌症患者和艾滋病毒/艾滋病患者，它们非常重要。然而，耐多药细菌的传播使这些治疗无效。在世界各地，由抗菌素耐药性细菌引起的人和动物感染的数量正在以惊人的比例增加，迫切需要新的治疗方法。然而，事实证明，很难找到进入大肠杆菌、沙门氏菌和铜绿假单胞菌(称为革兰氏阴性菌)等细菌的抗生素。此外，在过去的几十年里，很少有新的抗生素进入市场。因此，寻找方法使耐药细菌对现有的抗菌剂敏感是一个非常有吸引力的策略。抗菌素耐药性是一个日益严重的问题，原因之一是细菌能够很容易地通过多种方式分享他们的遗传信息，包括质粒传播。质粒是可以从一个细菌细胞转移到另一个细菌细胞的遗传物质。这些质粒通常含有使细菌对抗菌剂产生抗药性的基因(称为抗菌素抗药性基因)。因此，细菌能够分享抗菌素耐药性。这在全球范围内发生，抗菌素耐药质粒迅速遍及全球，在世界范围内造成严重和难以治疗的感染。在这个项目中，我们将使用我们开发的一种新系统来发现从细菌种群中去除这些抗菌素耐药质粒的化合物。它可以在许多环境中使用，包括动物、病人、农业和废水处理。在动物方面，包括美国等高收入国家在内的许多国家都使用了大量的抗生素，这为耐药性的发展提供了平台。这种抵抗随后可能会蔓延到其他国家。我们的工作将减少细菌种群中抗菌素耐药性基因的数量，从而降低这些基因进入人类病原体的机会，在那里它们可能导致无法治疗的感染。这项研究中确定的化合物也可以用于清洁表面，特别是在抗生素耐药性普遍存在的医院。它们还可以用来消除废水、土壤、堆肥和农场中的抗生素耐药性基因。我们的工作也可以应用于患者常规使用抗生素治疗的医院。根据我们的工作开发的药物可以在抗生素治疗之前给患者服用，从而增加细菌对抗生素的敏感性。为了完成这项工作，我们组建了一支拥有各种不同技术专长的科学家团队。我们将共同努力，通过使细菌对我们现有的抗生素敏感，提供对抗菌素耐药性至关重要的新的科学信息和知识。最终，这项研究将对由抗生素耐药细菌引起的危及生命的感染患者的治疗产生健康益处。

Antibiotics and antimicrobials underpin modern human and veterinary medicine. They are commonly used not only to treat infections, but also prior to surgery, and are extremely important for vulnerable patients with reduced immune function, including the young, elderly, transplant, cancer, and HIV/AIDS patients. However, the spread of multidrug resistant bacteria is rendering these treatments ineffective. The number of infections in people and animals caused by antimicrobial resistant bacteria are increasing to alarming proportions around the world, and new treatments are urgently needed. However, it has proven very difficult to find antibiotics that get inside bacteria such as E. coli, Salmonella and Pseudomonas aeruginosa (called Gram-negative bacteria). Furthermore, over the last few decades very few new antibiotics have made it to the market. Therefore, finding ways to make resistant bacteria susceptible to already existing antimicrobials is a very attractive strategy. One of the reasons antimicrobial resistance is such a growing problem is that bacteria are able to easily share their genetic information through a number of ways, including plasmid transmission. Plasmids are pieces of genetic material that can be moved from one bacterial cell to another. These plasmids often contain genes that allow bacteria to become resistant to antimicrobials (termed antimicrobial resistance genes). Therefore, bacteria are able to share antimicrobial resistance. This occurs on a global scale, with antimicrobial resistance plasmids rapidly traversing the globe, causing serious and difficult to treat infections worldwide. In this project, we will use a novel system we have developed to discover compounds that get rid of these antimicrobial resistance plasmids from bacterial populations. This could be used in a number of settings including animals, patients, farming, and waste water treatment. In animals, large quantities of antibiotics are used in a number of countries including high income countries such as the USA, which provides a platform for resistance to develop. This resistance can then spread to other nations. Our work would reduce the number of antimicrobial resistance genes in bacterial populations, therefore reducing the chances that these genes would get into human pathogens, where they could cause untreatable infections. Compounds identified in this study could also be used to clean surfaces, especially in hospitals, where antibiotic resistance is prevalent. They could also be used to eliminate antibiotic resistance genes from waste water, soil, compost, and farms. Our work could also be applied in hospitals where patients are routinely treated with antibiotics. Drugs developed from our work could be given to patients prior to antibiotic therapy, thus increasing bacteria susceptibility to antibiotics. In order to complete this work we have assembled a team of scientists with expertise in a wide range of different techniques. We will work together to provide new scientific information and knowledge crucial to combating antimicrobial resistance, by making bacteria sensitive to the antibiotics we already have available. Ultimately, this research will have a health benefit on the treatment of patients with life-threatening infections caused by antibiotic resistant bacteria.