Determining how polymyxins kill bacteria

细菌引起许多不同的感染，这些感染可以迅速从轻微发展到危及生命。通常，短期的抗生素疗程就足以清除感染。然而，越来越多的感染是由能够抵抗许多不同类型抗生素的细菌引起的。世界卫生组织已经确定，最令人担忧的耐药细菌类型都是革兰氏阴性菌，它们的外细胞包膜由细胞壁隔开的两层脂质膜组成。这些细菌对许多不同种类的抗生素具有耐药性，包括全球最常用的抗生素-内酰胺类抗生素。许多细菌仍然容易感染的一类抗生素是多粘菌素，其中两种用于临床，多粘菌素B和多粘菌素E（通常称为粘菌素）。不幸的是，多粘菌素不像其他抗生素那样有效，而且经常损害患者的肾脏。此外，对多粘菌素的耐药性是一个日益严重的问题。部分原因是由于这些药物的使用增加，也因为一种被称为MCR的多粘菌素耐药性可以在细菌之间传播。多粘菌素通过靶向细菌表面一种叫做LPS的化学物质来破坏外膜。我们小组的工作表明，多粘菌素也通过靶向LPS破坏内膜，这种破坏是杀死细菌所必需的。然而，多粘菌素靶向内膜LPS造成损伤的原因尚不清楚，将在本提案中解决。在确定了多粘菌素如何杀死细菌之后，我们将研究多粘菌素耐药性如何保护细菌免受这类抗生素的侵害，以及与耐药性相关的成本。最后，我们发现一种叫做murepavadin的实验性抗生素可以使细菌对多粘菌素的杀伤非常敏感，包括对多粘菌素耐药的菌株。通过了解这是如何发生的，我们可以设计出逆转多粘菌素耐药性的策略。结合起来，该项目将提供多粘菌素如何杀死细菌，多粘菌素耐药性如何起作用以及如何逆转多粘菌素耐药性的见解。

Bacteria cause many different infections, which can rapidly progress from mild to life-threatening. Ordinarily, a short course of antibiotics is sufficient to clear the infection. However, an increasing number of infections are caused by bacteria that can resist many different types of antibiotics. The World Health Organisation has determined that the most worrying types of resistant bacteria are all Gram-negative, which have an outer cell envelope that consists of two lipid membranes separated by a cell wall. These bacteria are resistant to many different classes of antibiotics, including those known as beta-lactams, which are the most commonly used antibiotics globally.One type of antibiotic that many bacteria are still susceptible to are the polymyxins, of which two are used clinically, polymyxin B and polymyxin E (more commonly known as colistin). Unfortunately, polymyxins don't work as well as other antibiotics and often damage the patient's kidneys. Furthermore, resistance to polymyxins is an ever-increasing problem. This is partly due to increased use of these drugs and also because a type of polymyxin resistance known as MCR can spread between bacteria.Polymyxins damage the outer membrane by targeting a chemical called LPS on the surface of bacteria. Work from our group revealed that polymyxins also damage the inner membrane by targeting LPS and that this damage is required to kill bacteria. However, the reasons why polymyxin targeting of LPS in the inner membrane causes damage is unclear and will be resolved in this proposal. Having determined how polymyxins kill bacteria, we will then investigate how polymyxin resistance protects bacteria from this class of antibiotics, as well as the costs associated with resistance.Finally, we have discovered that an experimental antibiotic called murepavadin can make bacteria very sensitive to killing by polymyxins, including strains that are polymyxin resistant. By understanding how this happens, we can devise strategies to reverse polymyxin resistance.Combined, this project will provide insight into how polymyxins kill bacteria, how polymyxin resistance functions and how polymyxin resistance can be reversed.