Exploitation of quorum sensing for the discovery of novel agents against staphylococci

多种抗生素耐药细菌的出现、迅速传播和持续存在对全球健康构成威胁。世界卫生组织指出？没有哪个人群比住院患者更容易对多种抗生素产生耐药性。在英国，与医疗保健相关的感染每年造成5000多人死亡，并给个人、家庭和NHS带来巨大的个人和经济成本（估计每年超过10亿美元）。在这种情况下，医院获得性耐甲氧西林金黄色葡萄球菌（HA-MRSA）和艰难梭菌都是特别有问题的。这不仅是因为它们有能力引起疾病，还因为抗生素的使用增加了耐药性和感染率。最近新？社区获得性?MRSA菌株（CA-MRSA）已经出现，可引起健康年轻人的侵袭性感染。在这种背景下，新型抗生素的开发远远落后于对新药的迫切需求，部分原因是主要制药公司不愿开发昂贵的新药，这些新药可能因耐药性而迅速过时。因此，如果我们要发现预防和治疗感染和减少耐药菌株选择的新方法，我们就需要更好地了解细菌的感染特异性生活方式。在这个项目中，我们试图了解MRSA细菌是如何利用化学信号相互沟通，从而决定何时部署它们所需的毒素军械库，以抵抗人类宿主的防御，在人类细胞内生长并破坏组织。通过了解这些信号的化学性质，细菌细胞产生这些信号并被细菌细胞表面的受体蛋白感知的方式，我们将开发出能够通过阻断这种信号系统来控制感染的新药物分子。到目前为止，我们已经发现了三种不同的小分子家族，它们要么抑制信号传导，要么抑制生长，要么两者兼而有之。因此，我们将使用药物化学和生物学方法来了解这些化合物在分子水平上是如何起作用的，并利用这些信息来设计在实验室抗菌试验中具有更高效力的药物。最有希望的化合物将在实验动物感染模型中进行功效测试。这项工作主要集中在MRSA上，但也将对有希望的化合物进行艰难梭菌和相关病原体的测试。

The emergence, rapid spread and persistence of multi-antibiotic resistant bacteria constitutes a global health threat. The World Health Organization has stated that ?no population is more vulnerable to multi-antibiotic resistance than those admitted to hospital wards?. In the UK, healthcare associated infections account for over 5000 deaths annually and are associated with enormous personal and financial costs to the individual, their family and to the NHS (estimated at over #1 billion p.a.). In this context, both hospital-acquired methicillin-resistant Staphylococcus aureus (HA-MRSA) and Clostridium difficile are particularly problematic. This is not only a consequence of their ability to cause disease but also because antibiotic usage increases resistance and infection rates. Recently new ?community acquired? MRSA strains (CA-MRSA) have emerged which cause invasive infections in healthy young people. Against this backdrop, the development of new classes of antibiotics has lagged far behind the urgent requirement for new drugs, in part because of the reluctance of major pharmaceutical companies to develop expensive new drugs likely to become rapidly obsolete through resistance. Consequently we need to gain better insights into the infection-specific lifestyle of bacteria if we are to discover new ways of preventing and treating infection and reducing the selection of resistant strains. In this project we are seeking to understand how MRSA bacteria use chemical signals to communicate with each to make decisions about when to deploy the armoury of toxins they need to fight off human host defences, grow inside human cells and damage tissues. By understanding the chemical nature of these signals, the way in which they are produced by the bacterial cell and sensed by receptor proteins on the bacterial cell surface we will develop new drug molecules capable of controlling infection by blocking this signalling system. So far we have discovered three different families of small molecules which either inhibit signalling or growth or both. We will therefore use medicinal chemistry and biological approaches to understand how these compounds work at the molecular level and use this information to design agents with increased potency in antibacterial assays in the laboratory. The most promising compounds will be tested for efficacy in experimental animal infection models. The work with focus on primarily MRSA but promising compounds will also be tested against C. difficile and related pathogens.