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

金属已被用于控制农业，食品处理，家庭卫生，医药中的微生物，更广泛地作为添加剂来保存易腐食品。工业合作伙伴宝洁公司正在实施开发新的金属基杀菌剂的计划，以取代现有的防腐剂，并提高现有金属基抗菌剂的功效（确保遵守不断变化的立法准则）。离子载体可以帮助最小化添加到产品中的金属量，并且有兴趣使用金属和/或螯合剂的更微妙的组合。从历史上看，金属的开发一直是经验性的，但天然金属基抗菌机制和细菌系统的发现，感觉和适应金属，提供了机会，以改善这些添加剂分别通过模仿和颠覆。金属涉及几种天然抗菌机制。例如，宿主和病原体已经进化为竞争铁。感染后约8小时，铜被泵入巨噬细胞的吞噬溶酶体区室，最有可能作为杀生物剂驱动芬顿反应。中性粒细胞被认为通过释放金属结合蛋白钙卫蛋白来使微生物缺乏锌和锰。细菌（与所有其他类型的细胞一样）已经进化出复杂的稳态机制，以在临界阈值内平衡各种金属的缓冲细胞内浓度;这对于确保大量金属蛋白获得正确的金属辅因子至关重要。这种金属稳态的核心是一组金属传感蛋白，它们可以检测何时超过缓冲限制。传感器触发蛋白质的表达，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”感知哪些金属的特性之后，下一步是研究体内金属特异性（传感器在细胞内“确实”感知的金属）是如何成为一组金属传感器的共享功能的。我们将开始模拟不同传感器蛋白之间的相互作用网络。该计划将探索金属细胞生物学的一个基本问题，碰巧提供了制定颠覆细菌金属传感网络的添加剂所需的见解。

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.