Developing a new class of antibiotics based on efflux resistant 4-oxoquinolizines for multidrug-resistant ESKAPE pathogens

开发基于抗外排 4-氧代喹嗪类的新型抗生素，用于治疗多重耐药 ESKAPE 病原体

• 批准号: MR/W018594/1
• 负责人: J. Mark Sutton
• 金额: $ 93.01万
• 依托单位: Public Health England
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW018594%2F1
• 关键词: Developing; new; class; antibiotics; based

Antibiotics have been a mainstay of modern medicine of the last 60 years and have been the principle means of treating infections. Although not a new problem, there is increasing evidence that antibiotics are becoming less effective in certain settings, due to the emergence of bacteria which are no longer susceptible to treatment with antibiotics. This is defined as antibiotic / antimicrobial resistance, AMR. In recent years there has been a rapid rise in bacteria which are resistant to multiple antibiotics, leading in some cases, to essentially untreatable infections associated with high mortality. These so-called multidrug resistant (MDR) bacteria come from a variety of different species and are a major cause for concern. There are a wide range of documents which aim to define this phenomenon, understand what impact it will have on public health worldwide, estimate the likely costs of AMR and identify solutions to the problem. These include research strategy documents from the Department of Health and Social Care, a review of AMR commissioned by the UK government (the AMR Review chaired by Lord O'Neil) and recent documents from the World Health Organisation, European Union, and Centres for Disease Control in the US. A common feature in AMR is the ability of bacteria to increase the presence or abundance of certain proteins which are able to pump an antibiotic out of the bacterial cell, which stops them working. These so-called "efflux pumps" are common and can work on many different types of antibiotic. Although an attractive approach would be block these pumps to stop them working, using efflux-pump inhibitors (EPIs), this has proved to be difficult to achieve. This is at least partly due to the toxicity of some of the drugs that have been tried in this context. The project team have developed a new approach which uses state of the art computational methods to identify where and how different molecules bind to the efflux pumps. The team identified that inhibitors bind to specific parts of the pump which are different from antibiotics that may be exported through the pump. This has led to a new approach, where hybrid molecules are made, which keep the active part of the antibiotic and add on specific parts of the inhibitor molecule. This means the modified antibiotics can no longer be exported from the cell, which makes them work better. This approach is applied here to a new class of antibiotics that have not been used in the clinic previously and this potentially allows us to bring a new class of antibiotics into clinical use. We will focus on a high priority group of bacteria, which were identified previously by WHO as those most urgently needing new antibiotics. These bacteria are associated with lung infections, especially in hospital environments, and patients who are infected may have very poor outcomes with current treatment. Although focussed on a very specific class of new antibiotics, the method can be used with other types of antibiotic and we have already proved this in the laboratory. This means that findings from this study may be useful for other drug developers and may contribute to improved approaches for antibiotic development.

在过去的60年里，抗生素一直是现代医学的中流砥柱，一直是治疗感染的主要手段。虽然不是一个新问题，但越来越多的证据表明，由于不再对抗生素治疗敏感的细菌的出现，抗生素在某些环境中变得不那么有效。这被定义为抗生素/抗菌素耐药性，AMR。近年来，对多种抗生素具有抗药性的细菌数量迅速上升，在某些情况下，导致基本上无法治愈的感染，并伴随着高死亡率。这些所谓的多药耐药(MDR)细菌来自各种不同的物种，是一个令人担忧的主要原因。有许多文件旨在定义这一现象，了解它将对世界各地的公共卫生产生什么影响，估计AMR的可能成本，并确定问题的解决方案。这些文件包括英国卫生和社会保障部的研究战略文件、英国政府委托进行的AMR评估(由奥尼尔勋爵主持的AMR评估)，以及世界卫生组织、欧盟和美国疾病控制中心最近发布的文件。AMR的一个共同特征是细菌能够增加某些蛋白质的存在或丰富，这些蛋白质能够将抗生素泵出细菌细胞，从而停止它们的工作。这些所谓的“外排泵”很常见，可以对许多不同类型的抗生素起作用。虽然一个有吸引力的方法是使用外排泵抑制剂(EPI)阻断这些泵的工作，但事实证明这很难实现。这至少部分是由于在这种情况下试验的一些药物的毒性。项目团队已经开发出一种新的方法，它使用最先进的计算方法来确定不同的分子在哪里以及如何与外排泵结合。研究小组发现，抑制剂与泵的特定部分结合，不同于可能通过泵出口的抗生素。这导致了一种新的方法，即制造杂化分子，保留抗生素的活性部分，并添加抑制分子的特定部分。这意味着修改后的抗生素不能再从细胞中输出，这使它们发挥更好的作用。这种方法被应用于一类以前没有在临床上使用过的新的抗生素，这可能使我们将一种新的抗生素带入临床使用。我们将把重点放在一组高度优先的细菌上，这些细菌以前被世卫组织确定为最迫切需要新抗生素的细菌。这些细菌与肺部感染有关，特别是在医院环境中，被感染的患者使用目前的治疗方法可能会有非常差的结果。虽然专注于一类非常特殊的新抗生素，但该方法可以与其他类型的抗生素一起使用，我们已经在实验室证明了这一点。这意味着这项研究的发现可能对其他药物开发商有用，并可能有助于改进抗生素开发的方法。