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

抗生素在过去60年中一直是现代医学的支柱，并且一直是治疗感染的主要手段。虽然这不是一个新问题，但越来越多的证据表明，抗生素在某些情况下变得不那么有效，因为出现了不再对抗生素治疗敏感的细菌。这被定义为抗生素/抗菌素耐药性，AMR。近年来，对多种抗生素具有耐药性的细菌迅速增加，在某些情况下导致与高死亡率相关的基本上无法治疗的感染。这些所谓的多药耐药（MDR）细菌来自各种不同的物种，是引起关注的主要原因。有大量文件旨在定义这一现象，了解其对全球公共卫生的影响，估计AMR的可能成本并确定问题的解决方案。其中包括卫生和社会保健部的研究战略文件，英国政府委托进行的AMR审查（由奥尼尔勋爵主持的AMR审查）以及世界卫生组织，欧盟和美国疾病控制中心的最新文件。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度，这些蛋白质能够将抗生素从细菌细胞中泵出，从而阻止它们工作。这些所谓的“外排泵”很常见，可以作用于许多不同类型的抗生素。虽然一个有吸引力的方法将是阻止这些泵停止工作，使用流出泵抑制剂（EPI），这已被证明是难以实现的。这至少部分是由于在这种情况下试用的一些药物的毒性。该项目团队开发了一种新方法，该方法使用最先进的计算方法来确定不同分子在何处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，这与可能通过泵输出的抗生素不同。这导致了一种新的方法，即制造杂交分子，保留抗生素的活性部分并添加抑制剂分子的特定部分。这意味着经过修饰的抗生素不能再从细胞中输出，这使得它们更好地发挥作用。这种方法在这里被应用于一种新的抗生素，这种抗生素以前没有在临床上使用过，这可能使我们能够将一种新的抗生素带入临床使用。我们将重点关注一组高度优先的细菌，世卫组织以前将其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，感染的患者在目前的治疗中可能会有非常差的结果。虽然该方法专注于一类非常特殊的新抗生素，但它也可以用于其他类型的抗生素，我们已经在实验室中证明了这一点。这意味着这项研究的发现可能对其他药物开发人员有用，并可能有助于改进抗生素开发方法。

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.