Unravelling the Bam complex

微生物对抗生素等抗微生物疗法的耐药性日益增加，是一个重大的全球公共卫生问题。据估计，仅在欧洲，这一问题每年就会导致25 000人死亡，每年可避免的住院天数约为250万天，经济负担估计至少为12亿英镑。革兰氏阴性菌的耐药性最为严重，基本上没有正在开发或可能在不久的将来可用于临床的抗生素。英国政府首席医疗官Dame Sally Davies教授最近的一份报告将其比作“定时炸弹”，并警告说，如果我们失去抵抗感染的能力，常规手术可能在短短20年内就会致命。了解革兰氏阴性细菌的细胞包膜对开发新的抗菌药物至关重要。所有革兰氏阴性菌都有两层膜包裹着细胞，被称为周质的空间隔开。这两层膜的外层特别能抵抗小分子的渗透。这种膜的主要功能是形成一个半透层，保护细菌免受环境的影响，同时也控制分子进出细胞的运动以及细胞如何与环境相互作用。正是这种膜内的蛋白质通过提供必要的生理、致病和耐药功能来控制这些机制，因此它们是微生物战争的工具，因为它们介导了许多导致感染和疾病进展的致命过程。确定能够阻止这种膜形成的化合物可能会导致下一代抗菌剂的开发。最近，一种被称为Bam复合体的蛋白质复合体被确定为负责大多数（如果不是全部的话）蛋白质的折叠和插入外膜，因此已被确定为该膜形成的关键瓶颈。因此，了解这一复合物的工作原理至关重要，因为设计抑制这一过程的化合物将抑制外膜蛋白的生物生成，从而抑制必不可少的生理、致病和耐药功能，并可能在对抗多种革兰氏阴性病原体方面发挥作用。在这个研究项目中，我们计划描述Bam复合体为了将蛋白质折叠到外膜中而进行的机制过程，我们将识别在外膜蛋白质插入过程中形成的配体相互作用位点和结合袋，从而提供有价值的机制见解，这将有助于发现分子抑制剂和新型抗菌剂。

The growing resistance of micro-organisms to antimicrobial therapies, such as antibiotics, is a significant global public health issue. In Europe alone this is currently estimated to result in an additional 25,000 deaths each year, approximately 2.5 million avoidable days in hospital and an economic burden estimated to be at least £1.2 Billion per year. Resistance is most serious for Gram-negative bacteria, with essentially few antibiotics under development or likely to be available for clinical use in the near future. A recent report by Professor Dame Sally Davies, the Government's Chief Medical Officer, likened it to a 'ticking time bomb' and warned that routine operations could become deadly in just 20 years if we lose the ability to fight infection.The understanding of the Gram-negative bacterial cell envelope is critical to developing new antimicrobial agents. All Gram-negative bacteria possess two membranes that enclose the cell, separated by a space known as the periplasm. The outer of the two membranes is particularly resistant to the penetration of small molecules. The main function of this membrane is to form a semi-permeable layer that protects the bacterium from the environment but also to control the movement of molecules into and out of the cell and how the cell interacts with its environment. It is the proteins within this membrane that control these mechanisms by providing essential physiological, pathogenic and drug resistance functions and hence are the instruments of microbial warfare as they mediate many of the lethal processes responsible for infection and disease progression. Identifying compounds that can prevent the formation of this membrane could lead to the development of the next generation of antimicrobials. Recently a single protein complex called the Bam complex was identified as being responsible for the folding and insertion of most if not all of the proteins into the outer membrane and hence has been identified as a key bottleneck in the formation of this membrane. Understanding how this complex works is therefore critical as the design of compounds that inhibit this process would inhibit outer membrane protein biogenesis and therefore essential physiological, pathogenic and drug resistance functions and could prove useful in combating diverse Gram-negative pathogens.In this research project we plan to characterise the mechanistic processes the Bam complex undertakes in order to fold proteins into the outer membrane, we will identify ligand interaction sites and binding pockets that form during outer membrane protein insertion and thus provide valuable mechanistic insights that will aid in the discovery of molecular inhibitors and new classes of antimicrobial agents.