Insights into the Antibacterial Mechanism of Action of Chelating Agents by Selective Deprivation of Iron, Manganese, and Zinc.
Insights into the Antibacterial Mechanism of Action of Chelating Agents by Selective Deprivation of Iron, Manganese, and Zinc.
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DOI：
10.1128/aem.01641-21
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发表时间：
2022-01-25
影响因子：
4.4
通讯作者：
Sharples GJ
中科院分区：
文献类型：
--
作者：
Paterson JR;Beecroft MS;Mulla RS;Osman D;Reeder NL;Caserta JA;Young TR;Pettigrew CA;Davies GE;Williams JAG;Sharples GJ
细菌的生长和增殖可以通过限制其环境中金属离子的可用性来限制。人类螯合铁，锰和锌，以帮助防止病原体感染，这一系统称为营养免疫。商业上使用的螯合剂与各种金属离子具有高结合亲和力，这可能导致模拟这些先天免疫过程的抗菌特性。然而，这些螯合剂中的许多在细菌生长抑制中的作用模式和它们在细胞中的金属剥夺中的选择性仍然不清楚。我们通过研究11种螯合剂对大肠杆菌生长的影响以及它们对五种金属的细胞浓度的影响来解决这个缺点。发现了以下四种不同的影响：（i）金属成分没有明显的变化，（ii）锰的消耗伴随着铁和锌水平的降低，（iii）锌水平降低，锰水平适度降低，以及（iv）铁水平降低伴随锰水平升高。这些效应与溶液中绝对已知的螯合剂金属离子亲和力无关;然而，对于至少五种可获得关键数据的螯合剂，它们可以通过螯合剂对每种金属离子的相对亲和力的差异来解释。结果揭示了螯合剂抑制生长的机制的重要见解，突出了它们作为抗菌剂的潜力，并作为探测细菌如何耐受选择性金属剥夺的工具。重要性螯合剂广泛用于工业和消费品中，以控制金属的可用性，限制细菌生长是保存的第二个好处。然而，螯合剂的抗菌作用机制在很大程度上是未知的，特别是关于对细胞金属浓度的影响。这里提出的工作揭示了不同的螯合剂对模型革兰氏阴性细菌大肠杆菌施加不同的金属饥饿效应。螯合剂进行了单独和成对的研究，大多数产生协同效应的组合，最大限度地提高抗菌敌意。基于对比细胞效应的螯合剂的明智选择应该能够减少许多商业产品中所需的螯合剂的量，并提供用可生物降解的替代品取代有问题的化学品的机会。
Bacterial growth and proliferation can be restricted by limiting the availability of metal ions in their environment. Humans sequester iron, manganese, and zinc to help prevent infection by pathogens, a system termed nutritional immunity. Commercially used chelants have high binding affinities with a variety of metal ions, which may lead to antibacterial properties that mimic these innate immune processes. However, the modes of action of many of these chelating agents in bacterial growth inhibition and their selectivity in metal deprivation in cellulo remain ill-defined. We address this shortcoming by examining the effect of 11 chelators on Escherichia coli growth and their impact on the cellular concentration of five metals. The following four distinct effects were uncovered: (i) no apparent alteration in metal composition, (ii) depletion of manganese alongside reductions in iron and zinc levels, (iii) reduced zinc levels with a modest reduction in manganese, and (iv) reduced iron levels coupled with elevated manganese. These effects do not correlate with the absolute known chelant metal ion affinities in solution; however, for at least five chelators for which key data are available, they can be explained by differences in the relative affinity of chelants for each metal ion. The results reveal significant insights into the mechanism of growth inhibition by chelants, highlighting their potential as antibacterials and as tools to probe how bacteria tolerate selective metal deprivation. IMPORTANCE Chelating agents are widely used in industry and consumer goods to control metal availability, with bacterial growth restriction as a secondary benefit for preservation. However, the antibacterial mechanism of action of chelants is largely unknown, particularly with respect to the impact on cellular metal concentrations. The work presented here uncovers distinct metal starvation effects imposed by different chelants on the model Gram-negative bacterium Escherichia coli. The chelators were studied both individually and in pairs, with the majority producing synergistic effects in combinations that maximize antibacterial hostility. The judicious selection of chelants based on contrasting cellular effects should enable reductions in the quantities of chelant required in numerous commercial products and presents opportunities to replace problematic chemistries with biodegradable alternatives.