Antibacterial activity and mechanism of action of semi-synthetic cocktail formulated from the Bald's eyesalve

由于与耐药感染相关的高死亡率和经济损失，抗生素耐药感染，特别是与生物膜相关的耐药感染，继续造成全球健康挑战。囊性纤维化患者的慢性伤口感染和肺部感染每年分别造成2810亿美元和7509亿美元的经济负担。在发现抗生素之前，感染通常用不同天然产物的组合来治疗。我们的实验室已经确定了一种中世纪的补救措施，称为“秃头的眼药”，用于治疗眼睛感染。该药物已显示出对创伤和肺部病原体的渗透性和生物膜形式的广谱活性。从我们实验室已经获得的初步数据开始，我们的计划是配制一种半合成鸡尾酒，只包含赋予这种复杂配方生物活性的化合物。我们将把复杂的治疗方法缩小到一组半合成或全合成的天然产物混合物，并测试这些混合物在伤口和肺生物膜模型中根除金黄色葡萄球菌和铜绿假单胞菌生物膜的能力。这将使我们能够制定一个最终的，化学定义的鸡尾酒，可用于治疗感染。此外，我们将确定我们的鸡尾酒对上述两种病原体的作用机制。我们还将通过将其与其他抗菌剂结合来增强我们的鸡尾酒的活性，并评估其治疗用途的安全性。该项目将为通过天然和合成形式的不同生物活性化合物的组合来测试天然产品的抗微生物活性铺平道路。

Antimicrobial-resistant infections, especially those associated with biofilms, continue to create a global health challenge due to the high mortality and economic loss associated with drug-resistant infections. Chronic wound infections and lung infections in people with cystic fibrosis both pose annual economic burdens of $281Bn and $7509Bn respectively. Prior to the discovery of antibiotics, infections were often treated with combinations of different natural products. Our lab has identified a medieval remedy called "Bald's eyesalve" which was used to treat eye infections. This remedy has shown broad-spectrum activities against planktonic and biofilm forms of wound and lung pathogens. Starting from preliminary data already obtained in our lab, our plan is to formulate a semi-synthetic cocktail comprising only the compounds that give this complex recipe its biological activity. We will narrow down the complex remedy to a set of semi-synthetic or fully synthetic mixtures of natural products, and test the ability of these cocktails to eradicate biofilms of Staphylococcus aureus and Pseudomonas aeruginosa in wound and lung biofilm models. This will allow us to formulate a final, chemically defined cocktail that could be used to treat infections. Furthermore, we will determine the mechanism of action of our cocktail against the two pathogens mentioned. We will also look to enhance the activity of our cocktail by combining it with other antimicrobials, and to assess its safety profile for therapeutic use. This project will pave way for a new approach to testing the antimicrobial activity of natural products through the combination of different bioactive compounds in their natural and synthetic forms.