Elucidation of the molecular basis of pseudoresistance to antibiotics in Staphylococcus aureus

阐明金黄色葡萄球菌对抗生素假耐药性的分子基础

• 批准号: G0501247/1
• 负责人: Alex O'Neill
• 金额: $ 38.35万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0501247%2F1
• 关键词: Elucidation; molecular; basis; pseudoresistance; antibiotics

The discovery of antibiotics in the early part of the 20th century made possible for the first time the treatment and cure of bacterial infections, and heralded a new era for humanity. However, the utility of these compounds has been progressively eroded as bacteria have evolved to resist their effects. Increases in antibiotic resistance prevent effective treatment of bacterial infections, and are associated with significantly greater illness and death of patients. Consequently, major strain is placed on the healthcare system and the adverse effects are felt throughout society as a whole. This is especially true for what is arguably the most important ?superbug?, Staphylococcus aureus. This organism causes a wider array of infections than any other bacterium, and the number of effective drugs available to treat the infections it causes is rapidly dwindling. Ordinarily, S. aureus becomes resistant as a result of permanent changes to its genetic make-up that allow it to grow in the presence of antibiotics. However, all S. aureus strains frequently display ?pseudoresistance? (PR) to antibiotics, a state in which the bacteria are unable to grow but are not killed, allowing them to resume growth when antibiotic treatment stops. The most important of these PR mechanisms are biofilms and antibiotic tolerance. The former describes films of bacteria growing on biological or inert surfaces (e.g. human tissue, indwelling medical devices), while the latter describes a type of PR which can be achieved by more than one route. These PR mechanisms are extremely important, since they occur frequently (e.g. biofilms occur in two-thirds of human infections, and tolerance is seen in two-thirds of strains isolated from patients with a S. aureus heart-valve infection), and both result in treatment failure with antibiotics. This project aims to understand exactly how these PR mechanisms prevent antibiotics from effectively killing bacteria. This information is essential for guiding the development of strategies and/or drugs that could allow PR to be circumvented. Dissection of the molecular basis of PR will shed light on bacterial processes that can be blocked or perhaps themselves be targeted by new antibacterial drugs. The potential for developing strategies aimed at preventing the formation of intractable biofilms on medical devices such as intravenous catheters, an extremely common cause of hospital infection, will be particularly valuable.

世纪早期抗生素的发现首次使细菌感染的治疗和治愈成为可能，并预示着人类进入了一个新时代。然而，这些化合物的效用已逐渐受到侵蚀，因为细菌已经进化到抵抗它们的作用。抗生素耐药性的增加阻碍了细菌感染的有效治疗，并与患者的疾病和死亡显著增加有关。因此，卫生保健系统承受了巨大的压力，整个社会都感受到了不利影响。对于可以说是最重要的东西来说，这一点尤其如此。超级细菌？金黄色葡萄球菌。这种微生物引起的感染比任何其他细菌都要广泛，并且可用于治疗它引起的感染的有效药物的数量正在迅速减少。通常，S。金黄色葡萄球菌由于其遗传组成的永久性变化而产生耐药性，使其能够在抗生素存在下生长。然而，所有S。金黄色葡萄球菌菌株经常显示？伪抵抗(PR)抗生素，在这种状态下，细菌无法生长，但没有被杀死，使它们能够在抗生素治疗停止时恢复生长。这些PR机制中最重要的是生物膜和抗生素耐受性。前者描述了在生物或惰性表面（例如人体组织，留置医疗器械）上生长的细菌膜，而后者描述了一种可以通过多种途径实现的PR类型。这些PR机制非常重要，因为它们经常发生（例如，生物膜出现在三分之二的人类感染中，并且在三分之二的从S.金黄色葡萄球菌心脏瓣膜感染），并且两者都导致抗生素治疗失败。该项目旨在确切了解这些PR机制如何阻止抗生素有效杀死细菌。这些信息对于指导开发可以规避PR的策略和/或药物至关重要。对PR分子基础的剖析将揭示可以被阻断的细菌过程，或者它们本身可能被新的抗菌药物靶向。开发旨在预防静脉内导管等医疗器械上形成难治性生物膜的策略的潜力将特别有价值，这是医院感染的一个非常常见的原因。