Bacterial copper handling: Opportunities for antimicrobial development

微量营养金属离子(铁、锰、锌、铜)对近一半蛋白质的功能是必不可少的，但如果过量存在或插入错误的位置，它们对细胞是有毒的。在所谓的“营养免疫”中，控制金属供应的战斗是宿主-病原体相互作用的关键组成部分，作为新的抗菌疗法，人们对开发控制营养金属水平和位置的药物越来越感兴趣。最近出现的宿主天然免疫细胞利用铜来杀死入侵的细菌。为了避免铜胁迫，大多数细菌都拥有铜耐受基因，这些基因编码一系列蛋白质，用于外排、运输(伴侣)和储存。这些基因有助于细菌的毒力，它们通常由铜传感器在转录上控制。广泛的电子搜索已经发现了奈瑟氏菌。(淋球菌被世界卫生组织列为最优先的全球病原体之一)是这一教条的一个例外。这种生物体中缺少一个可识别的铜传感器，也没有可识别的铜稳态系统。相反，编码假定的和已建立的铜蛋白的几个基因(包括铜外排泵)散布在整个基因组中，但它们在铜耐受性中的作用在很大程度上还没有得到测试。我们假设奈瑟氏菌使用了以前在其他细菌中未曾描述过的铜耐受的新机制。学生将使用跨越生物科学的跨学科方法来识别和描述这个系统的组成部分。

Trace nutrient metal ions (iron, manganese, zinc, copper) are essential for the function of nearly half of all proteins but they are toxic to cells if present in excess or if inserted into the wrong sites. The battle to control metal availability is a key component of host-pathogen interactions in so-called "Nutritional Immunity", and there is growing interest in developing agents that manipulate nutrient metal level and location as new antimicrobial therapeutics.It has recently emerged that host innate immune cells use copper to kill invading bacteria. To avoid copper stress, most bacteria possess copper tolerance genes that encode an array of proteins for efflux, trafficking (chaperones), and storage. These genes contribute to bacterial virulence, and they are usually transcriptionally controlled by a copper sensor. Extensive in silico searches have identified Neisseria sp. (N. gonorrhoeae is listed by the WHO amongst the highest priority global pathogens) as one exception to this dogma. A recognisable copper sensor is missing from this organism and there is no identifiable system for copper homeostasis. Instead, several genes encoding putative and established cuproproteins (including a copper efflux pump) are scattered throughout the genome but their roles in copper tolerance are largely untested. We hypothesise that Neisseria employs novel mechanisms for copper tolerance that have not been described previously in other bacteria. The student will identify and characterise components of this system using cross-disciplinary methods across the biosciences.