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

应用新工具识别革兰氏阴性菌中抗​​菌素耐药性质粒传播或稳定性的抑制剂

• 批准号: MR/N012933/1
• 负责人: Laura Piddock
• 金额: $ 25.54万
• 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: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN012933%2F1
• 关键词: Applying; New; Tools; Identify; Inhibitors

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.

抗生素和抗菌剂是现代人类和兽医学的基础。它们通常不仅用于治疗感染，而且用于手术前，并且对于免疫功能降低的脆弱患者（包括年轻人，老年人，移植，癌症和艾滋病毒/艾滋病患者）非常重要。然而，多重耐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，很难找到能进入大肠杆菌等细菌内部的抗生素。大肠杆菌、沙门氏菌和铜绿假单胞菌（称为革兰氏阴性菌）。此外，在过去的几十年里，很少有新的抗生素进入市场。因此，找到使耐药细菌对现有抗菌剂敏感的方法是一种非常有吸引力的策略。抗生素耐药性成为一个日益严重的问题的原因之一是细菌能够通过多种方式轻松共享其遗传信息，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。这些质粒通常含有允许细菌对抗菌剂产生耐药性的基因（称为抗菌剂耐药性基因）。因此，细菌能够共享抗菌素耐药性。这种情况在全球范围内发生，抗菌素耐药性质粒迅速穿越地球仪，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消除这些抗菌素耐药性质粒的化合物。这可以用于许多环境，包括动物，患者，农业和废水处理。在动物中，许多国家（包括美国等高收入国家）使用大量抗生素，这为耐药性的发展提供了平台。这种抵制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基因的数量，从而减少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愈的感染。在这项研究中发现的化合物也可用于清洁表面，特别是在医院，抗生素耐药性普遍存在。它们还可以用于消除废水，土壤，堆肥和农场中的抗生素抗性基因。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。从我们的工作中开发的药物可以在抗生素治疗之前给予患者，从而增加细菌对抗生素的敏感性。为了完成这项工作，我们组建了一个科学家团队，他们在各种不同的技术方面都有专业知识。我们将共同努力，通过使细菌对我们现有的抗生素敏感，提供对对抗抗菌素耐药性至关重要的新的科学信息和知识。最终，这项研究将对治疗由抗生素耐药性细菌引起的危及生命的感染患者产生健康益处。

项目成果

Clinically Relevant Plasmid-Host Interactions Indicate that Transcriptional and Not Genomic Modifications Ameliorate Fitness Costs of Klebsiella pneumoniae Carbapenemase-Carrying Plasmids.

• DOI: 10.1128/mbio.02303-17
• 发表时间: 2018-04-24
• 期刊: mBio
• 影响因子: 6.4
• 作者: Buckner MMC;Saw HTH;Osagie RN;McNally A;Ricci V;Wand ME;Woodford N;Ivens A;Webber MA;Piddock LJV
• 通讯作者: Piddock LJV

Strategies to combat antimicrobial resistance: anti-plasmid and plasmid curing.

• DOI: 10.1093/femsre/fuy031
• 发表时间: 2018-11-01
• 期刊: FEMS microbiology reviews
• 影响因子: 11.3
• 作者: Buckner MMC;Ciusa ML;Piddock LJV
• 通讯作者: Piddock LJV