The antimicrobial mode of action of tropolone: selective metal chelation and targeted inhibition of metalloenzymes

托波龙及其衍生物具有非苯类、7-碳环结构，长期以来一直被认为是有效的抗菌和抗真菌药物。最近的研究表明，它们可以作为多种金属酶的特异性抑制剂，包括酪氨酸酶、弹力酶、差向异构酶和烯醇化酶，它们与酶活性部位的金属阳离子结合以破坏功能。然而，在某些情况下，托波龙识别的酶并不是必不可少的，这表明多种金属酶可能以类似的方式作为靶点。关于这些化合物扰乱了哪些分子途径的细节仍不清楚。托波龙还具有金属螯合剂的功能，这一因素对抗菌活性的贡献还有待探索。初步研究表明，特罗普隆和与之关系密切的化合物--胡诺提醇(b-hujaplicin)对细菌中细胞金属水平的影响是不同的。这些结果表明，不同的孕酮的作用方式可能存在很大的差异，需要进一步的工作来准确地确定它们的金属酶靶标、受影响的代谢途径以及金属剥夺对抗菌活性的贡献。Tropolone对那些出了名的难以根除的物种非常有效，例如粘质沙雷氏菌和白色念珠菌。这两种微生物都是值得注意的机会性人类病原体，因此，除了对工业应用的好处外，更好地了解特罗波隆的多功能也将使其成为一种新的抗菌剂来对抗感染的潜力。本项目旨在确定曲普隆对粘质葡萄球菌和白色念珠菌的抗菌作用模式，并与宝洁产品中常规使用的螯合剂一起评估其活性。关于金属可获得性限制或对金属酶的特定影响而发现的作用模式的信息将有助于开发改进的配方，并提供关于如何破坏金属处理以提高抗菌效果的洞察。

Tropolone and its derivatives possess non-benzenoid, 7-carbon ring structures and have long been recognised as potent antibacterial and antifungal agents. Recent studies have revealed that they can function as specific inhibitors of a variety of metalloenzymes, including tyrosinases, elastases, epimerases and enolases, where they associate with the metal cation at the enzyme active site to disrupt functionality. However, in several cases the enzymes recognised by tropolone are not essential suggesting that multiple metalloenzymes may be targeted in a similar fashion. Details on which molecular pathways are disrupted by these compounds remain unclear. Tropolone also has the ability to function as a metal chelator and the contribution of this factor to antimicrobial activity has yet to be explored. Preliminary studies have revealed differing effects of tropolone and the closely related compound, hinokitiol (b-thujaplicin), on cellular metal levels in bacteria. These results suggest that there may well be differences in the mode of action of different tropolones and further work is needed to define precisely their metalloenzyme targets, the metabolic pathways affected and the contribution of metal deprivation to antimicrobial activity. Tropolones are highly effective against species that are notoriously difficult to eliminate, such as the bacterium Serratia marcescens and the fungus Candida albicans. Both organisms are notable opportunistic human pathogens, so in addition to benefits for industrial applications, a better understanding of the multifunctionality of tropolone will also inform its potential as a new antimicrobial agent to combat infections. This project aims to determine the antimicrobial mode of action of tropolone against S. marcescens and C. albicans and evaluate its activity in tandem with chelants routinely employed in P&G products. Information uncovered on the mode of action by restriction of metal availability or by specific effects on metalloenzymes will allow the development of improved formulations and offer insight into how metal handling can be disrupted to boost antimicrobial efficacy.