Metal-sensing in Salmonella: A model for targeting a network that differentiates metals

沙门氏菌金属传感：针对区分金属的网络的模型

• 批准号: BB/J017787/1
• 负责人: Nigel Robinson
• 金额: $ 68.49万
• 依托单位: Durham University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ017787%2F1
• 关键词: Metal; sensing; Salmonella; model; targeting

Metals have been used to control microbes in agriculture, food handling, domestic hygiene, medicine and more broadly as an additive to preserve perishables. The industrial partner, Procter and Gamble, have on-going programmes to develop new metal-based biocides to replace existing preservatives and to increase the efficacy of current metal-based anti-microbials (ensuring compliance with shifting legislative guidelines). Ionophores can help minimise the amount of metal added to products and there is interest in using more subtle combinations of metals and/or chelators. Historically, the exploitation of metals has been empirical but the discovery of natural metal-based antimicrobial mechanisms and of bacterial systems that sense and adapt to metals, presents opportunities to improve these additives through mimicry and subversion respectively.Metals are implicated in several natural anti-microbial mechanisms. For example hosts and pathogens have evolved to compete for iron. Copper is pumped into the phagolysosomal compartment of macrophages about eight hours post infection most probably as a biocide to drive the Fenton reaction. Neutrophils are thought to starve microbes of zinc and manganese by releasing the metal-binding protein calprotectin. Bacteria (in common with all other types of cells) have evolved elaborate homeostatic mechanisms to balance the buffered intracellular concentrations of various metals within critical thresholds; critical to ensure that vast numbers of metalloproteins acquire their correct metal-cofactors. Central to such metal homeostasis is a set of metal-sensing proteins that detect when the buffered limits have been exceeded. The sensors trigger expression of proteins that restore the correct metal-balance. Having discovered bacterial metal-sensors and identified properties that determine which metals they 'can' sense in vitro, the next step is to investigate how metal-specificity in vivo (the metals the sensors 'do' sense inside cells) is a shared function of a set of metal-sensors. We will begin to model the network of interactions between the different sensor proteins. This programme will explore a fundamental question central to the cell biology of metals, coincidentally providing insight needed to formulate additives that subvert bacterial metal-sensing networks.

金属已被用来控制农业、食品处理、家庭卫生、医药等领域的微生物，更广泛地说，金属被用作保存易腐物品的添加剂。工业伙伴宝洁公司正在进行方案，以开发新的金属基杀菌剂，以取代现有的防腐剂，并提高目前金属基抗微生物药的效力(确保遵守不断变化的立法准则)。离子载体可以帮助将添加到产品中的金属量降至最低，人们有兴趣使用更微妙的金属和/或螯合剂组合。从历史上看，金属的开发一直是经验性的，但天然金属抗菌机制的发现以及感知和适应金属的细菌系统的发现，分别为通过模仿和颠覆来改进这些添加剂提供了机会。金属与几种天然抗菌机制有关。例如，宿主和病原体已经进化为争夺铁。铜在感染后大约8小时被泵入巨噬细胞的吞噬小体隔间，最有可能的是作为一种杀生剂来驱动芬顿反应。中性粒细胞被认为通过释放金属结合蛋白钙保护素而使微生物缺乏锌和锰。细菌(与所有其他类型的细胞一样)进化出复杂的动态平衡机制，以平衡关键阈值内缓冲的各种金属的浓度；这对确保大量金属蛋白获得正确的金属辅因子至关重要。这种金属动态平衡的核心是一组金属感应蛋白质，它们可以检测缓冲极限何时被超过。传感器会触发蛋白质的表达，从而恢复正确的金属平衡。在发现了细菌金属传感器并确定了决定它们在体外可以感觉到哪些金属的特性后，下一步是研究体内金属特异性(传感器在细胞内能感觉到的金属)是一组金属传感器的共同功能。我们将开始对不同传感器蛋白之间的相互作用网络进行建模。该计划将探索金属细胞生物学的核心问题，巧合地提供了研制颠覆细菌金属传感网络的添加剂所需的洞察力。

项目成果

Fine control of metal concentrations is necessary for cells to discern zinc from cobalt.

• DOI: 10.1038/s41467-017-02085-z
• 发表时间: 2017-12-01
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Osman D;Foster AW;Chen J;Svedaite K;Steed JW;Lurie-Luke E;Huggins TG;Robinson NJ
• 通讯作者: Robinson NJ

Finding the right match

寻找合适的匹配

• DOI: 10.1038/s41570-019-0083-5
• 发表时间: 2019
• 期刊: Nature Reviews Chemistry
• 影响因子: 36.3
• 作者: Schilter D

Generating a Metal-responsive Transcriptional Regulator to Test What Confers Metal Sensing in Cells.

• DOI: 10.1074/jbc.m115.663427
• 发表时间: 2015-08-07
• 期刊: The Journal of biological chemistry
• 作者: Osman D;Piergentili C;Chen J;Chakrabarti B;Foster AW;Lurie-Luke E;Huggins TG;Robinson NJ
• 通讯作者: Robinson NJ

Metal preferences and metallation.

• DOI: 10.1074/jbc.r114.588145
• 发表时间: 2014-10-10
• 期刊: The Journal of biological chemistry
• 作者: Foster AW;Osman D;Robinson NJ
• 通讯作者: Robinson NJ

The Effectors and Sensory Sites of Formaldehyde-responsive Regulator FrmR and Metal-sensing Variant.

甲醛反应调节剂FRMR和金属感应变体的效应子和感觉位点。

• DOI: 10.1074/jbc.m116.745174
• 发表时间: 2016-09-09
• 期刊: The Journal of biological chemistry
• 作者: Osman D;Piergentili C;Chen J;Sayer LN;Usón I;Huggins TG;Robinson NJ;Pohl E
• 通讯作者: Pohl E