Bacterial copper handling: Opportunities for antimicrobial development

微量营养金属离子（铁、锰、锌、铜）对近一半的蛋白质的功能至关重要，但如果过量存在或插入错误的位点，则对细胞有毒。控制金属可利用性的斗争是所谓的“营养免疫”中宿主-病原体相互作用的关键组成部分，并且开发操纵营养金属水平和位置的试剂作为新的抗微生物治疗剂的兴趣越来越大。为了避免铜胁迫，大多数细菌具有铜耐受基因，其编码一系列用于流出、运输（伴侣）和储存的蛋白质。这些基因有助于细菌的毒力，并且它们通常由铜传感器转录控制。广泛的计算机检索已经鉴定出奈瑟氏菌属（N.淋病被WHO列为最优先的全球病原体之一）作为该教条的一个例外。这种生物缺少可识别的铜传感器，并且没有可识别的铜稳态系统。相反，几个基因编码的推定和建立铜蛋白（包括铜外排泵）分散在整个基因组，但他们在铜耐受性的作用在很大程度上是未经测试的。我们假设奈瑟菌采用了其他细菌中以前没有描述过的铜耐受性的新机制。学生将使用跨生物科学的跨学科方法来识别和分析该系统的组成部分。

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.