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

在英国，传染病曾经是几乎所有年龄段的男性和女性的主要死亡原因。然而，抗生素的发现彻底改变了我们治疗细菌感染的能力，因此拯救了数百万人的生命。细菌几乎存在于地球的每一个角落，因为它们具有令人难以置信的适应不同环境的能力。这种即使在最不适宜居住的环境中也能进化和生存的能力意味着，随着一种新的抗生素被引入我们的医疗系统，耐药细菌菌株迅速出现。这个循环一直在重复，直到在某些情况下出现了目前任何可用的抗生素都无法有效治疗的感染。这造成了一种危险的局面，“后抗生素”时代现在正在成为现实，威胁到从癌症治疗到牙科工作的医疗保健的方方面面。在可能导致多重耐药的病原体中，鲍曼不动杆菌处于领先地位。这种病原体可以感染已经患病或免疫系统受到抑制的人，导致各种威胁生命的临床并发症，甚至可能死亡。这造成了一个问题，特别是在鲍曼不动杆菌暴发最多的医院。在本世纪头十年之前，鲍曼不动杆菌感染相对较少，而且通常非常容易治疗。然而，这些感染的数量迅速增加，以至于这种细菌现在占全球重症监护病房(ICU)所有感染的20%。这些感染非常难以治疗，从这些患者中分离出的鲍曼不动杆菌中有75%对3种以上的抗生素具有耐药性。此前，我们已经证明，人工甜味剂安赛蜜K(ACES-K)是一种化合物，全世界数百万人每天在“无糖”或“无卡路里”的食物和饮料中消费，具有显著的抗击这种病原体的能力。我们证明了ACE-K不仅可以抑制这种病原体的生长。它还可以抑制它用来建立感染的一系列有毒过程，包括从初始感染部位移动的能力，以及这种细菌形成称为生物膜的群落的能力，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将使鲍曼不动杆菌对它之前进化出的抗药性的抗生素变得脆弱。我们现在想要探索ACE-K到底对细胞做了什么，以阻止它的生长，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准确揭示ACE-K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、表征和评估新型的ACE-K负载型伤口敷料，以治疗急性和长期的、难以治疗的感染，并在猪的体外伤口模型中进行测试。我们还将在小鼠伤口模型中测试这些加载的伤口敷料，以确定它们治疗感染的能力。由于ACE-K已被包括食品和药物管理局在内的所有国际监管机构批准使用，这意味着它已经经过了广泛的安全性测试。因此，使用ACE-K作为治疗感染的药物有很大的潜力，可以快速进入临床试验和医院。这将克服推迟推出新的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测试和试验平均可能需要15年以上的时间才能完成。

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.