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人群中男女死亡的主要原因。但是，抗生素的发现彻底改变了我们治疗细菌感染的能力，因此挽救了数百万的生命。细菌几乎居住在我们地球的每个角落，因为它们不可思议地适应了不同的环境壁ni。即使在最荒凉的环境中，这种发展和生存的能力也意味着，在引入新的抗生素对我们的医疗保健系统引入新的抗生素之后，抗药性细菌菌株迅速出现。这个周期一直在重复，直到在某些情况下出现无法用任何当前可用的抗生素进行有效治疗的感染。这造成了危险的情况，即“抗生素后”时代现在正成为现实，威胁着从癌症治疗到牙科工作的所有方面。在可以进化多药耐药性的病原体的最前沿是鲍曼尼杆菌。这种病原体会感染已经生病或患有抗抑郁的免疫系统的个体，导致各种威胁生命的临床并发症以及可能死亡。这会造成一个问题，尤其是在大多数鲍曼尼爆暴发的医院中。在2000年代之前，鲍曼尼曲霉的感染相对较少，通常非常可治疗。但是，这些感染的数量迅速增加，因此该细菌现在占全球重症监护病房（ICU）中所有感染的20％。这些感染难以治疗非常困难，从这些患者中分离出多达75％的鲍曼尼a。以前，我们已经表明，人造甜味剂aceSulfame k（ACE-K）每天都在世界各地数百万的人使用“无糖”或“无卡路里”食品和饮料消耗的化合物，具有出色的解决这种病原体的能力。我们证明，ACE-K不仅可以抑制这种病原体的生长。它还可以抑制其用于建立感染的一系列有毒过程，包括从最初的感染部位转移到该细菌的能力，形成称为生物膜的群落，从而有助于其克服抗生素疗法。值得注意的是，我们还证明了这种化合物将使鲍曼尼曲霉很容易受到以前具有抗生素的抗生素的影响。现在，我们想探索ACE-K对细胞的究竟做什么，以阻止其生长并提高其对抗生素的敏感性。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确切发现ACE-K如何影响细菌细胞并使其对抗生素进行敏感。我们将开发，表征和评估新型ACE-K负载的伤口敷料，以解决急性和长期，难以治疗感染并在猪外体内伤口模型中测试它们。我们还将在小鼠伤口模型中测试这些负载的伤口敷料，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消费，因此这意味着它已经过广泛的测试。因此，将ACE-K用作治疗性来应对感染的潜力很大，可以快速追踪到临床试验和医院。这将克服延迟引入新抗微生物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花费15年以上才能完成。