Uncovering the antimicrobial and antibiotic potentiating mechanism of acesulfame-K and maximising its topical therapeutic potential.

揭示安赛蜜的抗菌和抗生素增强机制并最大限度地发挥其局部治疗潜力。

• 批准号: MR/Y001354/1
• 负责人: Ronan McCarthy
• 金额: $ 79.06万
• 依托单位: Brunel University London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY001354%2F1
• 关键词: Uncovering; antimicrobial; antibiotic; potentiating; mechanism

Infectious diseases were once the leading cause of death amongst men and women in almost all age demographics in the UK. However, the discovery of antibiotics revolutionised our ability to treat bacterial infections and, as a result, saved millions of lives. Bacteria inhabit almost every corner of our planet due to their incredible ability to adapt to different environmental niches. This capacity to evolve and survive even in the most inhospitable environments means that, following the introduction of a new antibiotic to our healthcare systems, resistant bacterial strains rapidly appear. This cycle has kept repeating until the emergence, in some instances, of infections that cannot be effectively treated with any currently available antibiotics. This is creating a dangerous situation where a "post-antibiotic" era is now becoming a reality, threatening all aspects of healthcare from cancer treatment to dental work. At the forefront of pathogens that can evolve multidrug resistance is Acinetobacter baumannii. This pathogen can infect individuals who are already sick or have a supressed immune system, leading to a variety of life-threatening clinical complications and, potentially, death. This creates a problem particularly in hospitals where most A. baumannii outbreaks occur. Prior to the 2000s, A. baumannii infections were relatively infrequent and, typically, very treatable. However, there has been a rapid increase in the number of these infections, such that this bacterium now accounts for 20% of all infections seen in Intensive Care Units (ICUs) worldwide. These infections are incredibly difficult to treat, with up to 75% of A. baumannii isolated from these patients being resistant to more than 3 types of antibiotic. Previously, we have shown that the artificial sweetener acesulfame K (ace-K), a compound is consumed by millions of people around the world every day in "sugar free" or "calorie free" food and drinks, has a remarkable ability to tackle this pathogen. We demonstrated that not only can ace-K inhibit this pathogens growth. It can also inhibit a range of virulent processes that it uses to establish infection, including the ability to move from the initial site of infection and the capacity of this bacteria to form communities called biofilms which help it overcome antibiotic therapy. Remarkably, we also demonstrated that this compound will make A. baumannii vulnerable to antibiotics that it has previously evolved resistance to. We now want to explore what exactly ace-K is doing to the cell to stop it growing and to increase its sensitivity to antibiotics. We will use a range of cutting-edge fluorescent microscopy, proteomics and molecular biology techniques to uncover exactly how ace-k effects the bacterial cell and resensitises it to antibiotics. We will develop, characterise and assess novel ace-K loaded wound dressings to tackle acute and long-term, difficult to treat infections and test them in a porcine ex vivo wound model. We will also test these loaded wound dressings in a mouse wound model to determine their capacity to treat infection. As ace-k is approved for consumption by every international regulatory body including the Food and Drug Administration, it means it has been extensively tested for safety. Therefore, there is significant potential that the use of ace-K as a therapeutic to tackle infection could be fast tracked to clinical trials and into hospitals. This would overcome one of the main barriers delaying the introduction of new antimicrobials drugs which is that all the safety testing and trials required before final approval can take over 15 years on average to complete.

传染病曾经是英国几乎所有年龄段男女死亡的主要原因。然而，抗生素的发现彻底改变了我们治疗细菌感染的能力，从而挽救了数百万人的生命。细菌几乎栖息在我们星球的每个角落，因为它们具有适应不同环境的不可思议的能力。这种即使在最恶劣的环境中也能进化和生存的能力意味着，在我们的医疗系统中引入新的抗生素后，耐药菌株迅速出现。这种循环一直在重复，直到出现，在某些情况下，感染，不能有效地治疗任何现有的抗生素。这正在创造一种危险的局面，“后抗生素”时代正在成为现实，威胁着从癌症治疗到牙科工作的医疗保健的各个方面。鲍曼不动杆菌是能够产生多药耐药性的病原体的最前沿。这种病原体可以感染已经患病或免疫系统受到抑制的个体，导致各种危及生命的临床并发症，并可能导致死亡。这造成了一个问题，特别是在医院，大多数A。鲍曼不动杆菌爆发。在2000年之前，A。鲍曼不动杆菌感染相对罕见，并且通常是非常可治疗的。然而，这些感染的数量迅速增加，因此这种细菌现在占全球重症监护病房（ICU）中所有感染的20%。这些感染非常难以治疗，高达75%的A。从这些患者中分离的鲍曼不动杆菌对3种以上的抗生素具有耐药性。此前，我们已经证明，人工甜味剂乙酰磺胺酸钾（ace-K），一种每天被世界各地数百万人在“无糖”或“无卡路里”食品和饮料中消费的化合物，具有应对这种病原体的显着能力。我们证明了ace-K不仅可以抑制这种病原体的生长。它还可以抑制一系列用于建立感染的毒性过程，包括从感染的初始部位移动的能力以及这种细菌形成称为生物膜的社区的能力，这有助于它克服抗生素治疗。值得注意的是，我们还证明了这种化合物会使A。鲍曼不动杆菌易受抗生素的影响，而此前它已进化出耐药性。我们现在想探索ace-K究竟对细胞起了什么作用，以阻止它生长并增加它对抗生素的敏感性。我们将使用一系列尖端的荧光显微镜、蛋白质组学和分子生物学技术来揭示ace-k究竟是如何影响细菌细胞并使其对抗生素重新敏感的。我们将开发、验证和评估新型ace-K负载伤口敷料，以应对急性和长期难以治疗的感染，并在猪离体伤口模型中对其进行测试。我们还将在小鼠伤口模型中测试这些负载伤口敷料，以确定其治疗感染的能力。由于ace-k被包括食品和药物管理局在内的每个国际监管机构批准用于消费，这意味着它已经过广泛的安全性测试。因此，使用ace-K作为治疗感染的治疗方法可以快速跟踪到临床试验和医院，这是非常有潜力的。这将克服推迟引入新的抗菌药物的主要障碍之一，即在最终批准之前所需的所有安全性测试和试验平均需要15年以上才能完成。