Dissecting the role of a membrane-associated bacterioferritin complex in Neisseria gonorrhoeae

细菌感染是生活中的事实。抗生素大大降低了死亡率，但抗生素耐药性的蔓延可能会阻碍传染病的控制，并危及我们认为理所当然的医疗保健的基本方面。在英国，每年约有44,000人死于无法治愈的细菌感染，每年花费NHS 20亿英镑。铁是许多酶的重要辅助因子，细菌必须确保它们有足够的这种必需营养素供应。在受到微生物感染后，动物宿主的先天免疫系统通常会降低铁的可用性。作为回应，细菌激活金属进口、金属节约或金属储存的途径，以避免金属饥饿带来的压力。这种对金属的争夺被称为“营养免疫”。铁蛋白是所有生命体中主要的铁储存库，它们的作用是氧化铁，并将铁以一种生物可利用的矿物质形式隔离在一个中空的蛋白质笼子里。一些细菌拥有结合血红素的细菌铁蛋白，它允许通过血红素基团的电子转移快速动员储存的铁。本项目将重点研究革兰氏阴性淋病奈瑟菌膜相关细菌铁蛋白复合物。这种病原体已被确定为一种“超级细菌”，其多个菌株和分离株已对所有最后一线抗生素产生完全耐药性。毫不奇怪，这种病原体被美国疾病控制中心、世界卫生组织和英国公共卫生部列为研究重点。目标和目的：生产重组细菌铁蛋白复合物，用于结构和功能分析，以了解铁如何在隔室中储存。使用结构生物学技术，包括x射线晶体学和电子显微镜，分析细菌铁蛋白复合物的分子结构。在淋病奈瑟菌中对单个细菌铁蛋白组分进行靶向基因敲除，了解其在淋病奈瑟菌的生理和致病性中的作用。

Bacterial infection is a fact of life. Antibiotics have considerably reduced mortality, but the spread of antibiotic resistance threatens to impede infectious disease control and compromise basic aspects of healthcare that we take for granted. In the UK ~44,000 deaths occur every year from untreatable bacterial infections, costing the NHS £2 billion annually. Iron is a vital cofactor for many enzymes, and bacteria must ensure that they have an adequate supply of this essential nutrient. Upon infection by microorganisms, the animal host innate immune system typically reduces the availability of iron. In response, bacteria activate pathways for metal import, metal sparing, or metal storage to avoid stress from metal starvation. This competition for metals is termed "nutritional immunity". Ferritin proteins are the primary iron stores in all kingdoms of life, they act to oxidise and sequester iron in a bioavailable mineral form within a hollow protein cage. Some bacteria possess heme-binding bacterioferritins, which allow the rapid mobilisation of stored iron through electron transfer via the heme group. This project will focus on the study of a membrane associated bacterioferritin complex from the Gram-negative pathogen Neisseria gonorrhoeae. This pathogen has been identified as a "superbug", with multiple strains and isolates that have become completely resistant to all last-line antibiotics. It is not surprising that this pathogen is listed by the Centre of Disease Control (USA), the World Health Organisation, and Public Health UK as a research priority. Goals and Objectives: Produce recombinant bacterioferritin complexes, for structural and functional analyses to understand how iron is stored within the compartment. Use structural biology techniques, including X-ray crystallography and electron microscopy, to analyse the molecular structure of the bacterioferritin complex. Make targeted gene knockouts in Neisseria gonorrhoea of the individual bacterioferritin components to understand their role in the physiology and pathogenicity of this bacterium.