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

细菌感染是生活中不可缺少的事实。抗生素大大降低了死亡率，但抗生素耐药性的传播有可能阻碍传染病控制，并危及我们认为理所当然的基本医疗保健方面。在英国，每年约有44,000人死于无法治疗的细菌感染，每年花费NHS GB 20亿英镑。铁是许多酶的重要辅因子，细菌必须确保它们有足够的这种基本营养物质的供应。一旦被微生物感染，动物宿主的先天免疫系统通常会减少铁的可获得性。作为回应，细菌激活了金属进口、金属储备或金属储存的途径，以避免金属饥饿带来的压力。这种对金属的竞争被称为“营养免疫”。铁蛋白是所有生命王国中主要的铁储存，它们在中空蛋白笼中以生物可用矿物质的形式氧化和隔离铁。一些细菌拥有与血红素结合的细菌铁素，它允许通过血红素基团的电子转移来快速动员储存的铁。本项目将重点研究革兰氏阴性病原体淋球菌的膜相关细菌铁蛋白复合体。这种病原体已被鉴定为“超级细菌”，有多个菌株和分离株已对所有最后一线抗生素产生完全抗药性。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列为研究重点。目的和目的：生产重组细菌铁蛋白复合体，用于结构和功能分析，以了解铁是如何储存在隔室内的。使用结构生物学技术，包括X射线结晶学和电子显微镜，分析细菌铁蛋白复合体的分子结构。在淋病奈瑟菌中对单个细菌铁蛋白成分进行有针对性的基因敲除，以了解它们在这种细菌的生理学和致病性中的作用。

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.