The antibacterial mechanism of action of piroctone olamine against Staphylococcus aureus: effects on metal deprivation and membrane integrity

吡罗克酮乙醇胺（PO）是许多具有商业重要性的宝洁配方中的一种活性抗真菌和抗细菌成分，包括全球成功的海飞丝（H & S）和Safeguard品牌。尽管其功能性的公认价值，PO的作用机制是复杂的和知之甚少。由P & G和达勒姆进行的分子建模模拟表明，活性吡罗克酮组分具有穿过细菌膜并发挥细胞内作用的能力。也有迹象表明，它可以聚集在膜和破坏脂质双层的完整性。吡罗克酮是PO的金属结合单元，是一种环状异羟肟酸盐，类似于铁载体去铁胺的组成结合单元，其以高亲和力结合Fe（III）。事实上，我们与宝洁公司合作的多条证据表明，PO在剥夺革兰氏阴性大肠杆菌必需铁方面发挥了作用。然而，关于PO如何作为抗金黄色葡萄球菌（Staphylococcus aureus）的抗菌剂起作用还不知道，金黄色葡萄球菌是革兰氏阳性菌，其消除在P & G产品中是高度期望的。S.金黄色葡萄球菌是来自所谓的“ESKAPE”组的六种细菌病原体之一，其以多药耐药性和毒力而闻名。S.金黄色葡萄球菌是医院感染的常见原因，迫切需要开发替代疗法来对抗疾病。因此，除了对具有抗菌性能的消费品的明显益处外，更好地了解PO的作用方式将有助于评估其固有的抗菌性能，并作为其他抗菌剂的潜在佐剂。本项目旨在确定PO对S.金黄色葡萄球菌，并评估其与螯合剂和宝洁产品中常规使用的其他成分的功效。通过限制金属可用性或膜破坏而揭示的作用模式的信息将允许开发改进的制剂。

Piroctone olamine (PO) is an active antifungal and antibacterial ingredient in a number of commercially important P&G formulations, including the globally successful Head & Shoulders (H&S) and Safeguard brands. Despite the recognised value of its functionality, the mechanism of action of PO is complex and poorly understood. Molecular modelling simulations carried out by P&G and at Durham suggest that the active piroctone component has the capacity to traverse bacterial membranes and exert intracellular effects. There are also indications that it can aggregate at the membrane and disrupt lipid bilayer integrity. Piroctone, the metal binding unit of PO, is a cyclic hydroxamate that resembles the constituent binding units of the siderophore desferrioxamine, which binds Fe(III) with high affinity. Indeed, multiple lines of evidence from our partnership with P&G point to a role for PO in depriving Gram-negative Escherichia coli of essential iron. However, nothing is known concerning how PO functions as an antibacterial agent against Staphylococcus aureus, a Gram-positive whose elimination is highly desirable in P&G products. S. aureus is one of six bacterial pathogens from the so-called 'ESKAPE' group that are notable for multidrug resistance and virulence. S. aureus is a common cause of nosocomial infections and there is an urgent need to develop alternative therapeutics to combat disease. Hence, in addition to the clear benefits for consumer goods with antimicrobial properties, a better understanding of the mode of action of PO will aid in evaluation of its inherent antimicrobial properties and as a potential adjuvant for other antibacterial agents. This project aims to determine the antimicrobial mode of action of PO against S. aureus and evaluate its efficacy in tandem with chelants and other ingredients routinely employed in P&G products. Information uncovered on the mode of action by restriction of metal availability or membrane disruption will allow the development of improved formulations.