MICA: Understanding how bacteria respond to efflux inhibition

在世界各地，由抗生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，从历史上看，已经证明很难找到可以进入大肠杆菌等细菌的抗生素。大肠杆菌（称为革兰氏阴性菌）。即使它们渗透到细胞中，大多数也会被泵出/输出（称为“流出”）。这种输出是通过生物“真空吸尘器”将物质从细菌细胞内部吸到外部。一个单一的系统可以运输许多不同类型的抗生素。如果没有这样的系统，革兰氏阴性细菌会被非常低浓度的抗生素杀死。限制药物进入细菌细胞（称为外膜渗透性）和通过多药耐药（MDR）外排系统输出的组合是为什么如此多的抗生素是有效治疗革兰氏阳性细菌引起的感染的原因，例如金黄色葡萄球菌，对革兰氏阴性细菌不起作用。将抗生素运输出细胞的外排系统不仅需要产生抗生素抗性，而且没有它们，细菌无法引起感染或形成生物膜-一种生活在宿主和环境表面的细菌群落。外排抑制剂使细菌对抗生素非常敏感，使它们不太能够定植或感染宿主，也不太能够形成生物膜。因此，外排抑制剂提供了潜在的增加现有的和新的drugs.Our的目的是调查的假设，即耐药菌可以出现，即使在存在的外排抑制剂的有效性。在这个项目中，我们将建立在我们的初步数据，确定何时E。大肠杆菌对抗生素和外排抑制剂的组合产生耐药性。我们将确定细菌如何产生耐药性，并确定这种耐药性是否已经存在于从人和动物分离的细菌中。我们将使用一个模型来再现人体内药物水平随时间的变化，以确定抑制抗生素和外排抑制剂耐药性出现的方法。为了实现该项目的目标，有两名申请人，一名科学家和一名医生，以及来自制药行业和两所大学的三名专家合作者。我们将共同努力，提供新的科学信息和知识的药物发现外排抑制剂的关键。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。

The number of infections in people and animals caused by antibiotic resistant bacteria are increasing to alarming proportions around the world, and new treatments are urgently needed. However, historically, it has proven very difficult to find antibiotics that can get into bacteria such as E. coli (called Gram-negative bacteria). Even when they penetrate into the cell, most get pumped out/exported (called 'effluxed'). This export is via a biological 'vacuum cleaner' that sucks substances out of the inside to the outside of the bacterial cell. A single system can transport many different types of antibiotics. Without such systems Gram-negative bacteria are killed by very low concentrations of antibiotics. The combination of restricted entry of drugs into the bacterial cell (called outer membrane permeability) and export by multidrug resistance (MDR) efflux systems are why so many antibiotics that are effective treatments for infections caused by Gram positive bacteria, such as Staphylococcus aureus, do not work against Gram negative bacteria. Efflux systems that transport antibiotics out of the cell are not only required to give antibiotic resistance but without them bacteria are unable to cause an infection or form a biofilm - a community of bacteria that live on surfaces in the host and environment. Efflux inhibitors make the bacterium very sensitive to antibiotics, make them less able to colonise or infect their hosts and less able to form a biofilm. Therefore, efflux inhibitors offer the potential to increase the effectiveness of currently available and new drugs.Our aim is to investigate the hypothesis that drug-resistant bacteria can emerge even in the presence of an efflux inhibitor. In this project, we will build upon our preliminary data by determining when E. coli becomes resistant to a combination of an antibiotic and efflux inhibitor. We will identify how the bacteria become drug resistant and find out if this type of resistance already exists in bacteria isolated from people and animals. Using a model that reproduces drug levels over time in people, we will identify ways to suppress the emergence of antibiotic and efflux inhibitor resistance.To achieve the project aim, there are two applicants, a scientist and a doctor, plus three expert collaborators from the pharmaceutical industry and two universities. We will work together to provide new scientific information and knowledge crucial to the drug discovery of efflux inhibitors. Ultimately, this research will have a health benefit on the treatment of patients with life-threatening infections caused by antibiotic resistant bacteria.