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

吡洛酮醇胺(PO)是许多具有重要商业意义的宝洁配方中的有效抗真菌和抗菌成分，包括在全球获得成功的Head&Shoulds(H&S)和Safe品牌。尽管人们认识到PO的功能价值，但PO的作用机制复杂且知之甚少。宝洁公司和杜伦大学进行的分子模拟模拟表明，活性吡洛酮成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，它可以聚集在膜上，破坏脂质双层的完整性。吡洛酮是PO的金属结合单元，是一种环状异羟甲酸酯，类似于铁载体去铁胺的组成结合单元，它以高亲和力结合Fe(III)。事实上，我们与宝洁合作的多条证据表明，PO在剥夺革兰氏阴性大肠埃希菌必需的铁方面发挥了作用。然而，关于PO如何作为抗菌剂对抗金黄色葡萄球菌的作用尚不清楚，金黄色葡萄球菌是一种革兰氏阳性菌，在宝洁产品中消除它是非常可取的。金黄色葡萄球菌是所谓的ESKAPE组中以多重耐药性和毒力著称的六种细菌之一。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具有明显的好处外，更好地了解PO的作用模式将有助于评估其固有的抗菌性能，并将其作为其他抗菌剂的潜在佐剂。本项目旨在确定PO对金黄色葡萄球菌的抗菌作用模式，并结合宝洁产品中常规使用的螯合剂和其他成分来评估其效果。由于金属可获得性限制或膜破坏而发现的作用模式的信息将有助于改进配方的开发。

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.