Determining how polymyxins kill bacteria

确定多粘菌素如何杀死细菌

• 批准号: BB/Y003667/1
• 负责人: Andrew Edwards
• 金额: $ 78.6万
• 依托单位: Imperial College 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=BB%2FY003667%2F1
• 关键词: Determining; how; polymyxins; kill; bacteria

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.

细菌引起许多不同的感染，这可能会从轻度到威胁生命。通常，短暂的抗生素足以清除感染。但是，越来越多的感染是由可抵抗许多不同类型的抗生素的细菌引起的。世界卫生组织已经确定，最令人担忧的抗性细菌都是革兰氏阴性菌，其外部细胞包膜由两个被细胞壁隔开的脂质膜组成。这些细菌对许多不同类别的抗生素具有抗药性，包括那些被称为β-内酰胺的抗生素，该抗生素是全球最常用的抗生素。一种类型的抗生素类型，许多细菌仍然易感的多聚染料是多聚淋巴素，其中两种是临床上使用的抗生素，其中两种是临床上使用的，多肌纤维纤维B和多聚糖蛋白E（通常称为colistins colistins）。不幸的是，多碳素的起作用不如其他抗生素，并且经常会损害患者的肾脏。此外，对多碳素的耐药性是一个不断增加的问题。这部分是由于这些药物的使用增加，也是由于一种称为MCR的多牙蛋白耐药性可以在细菌之间扩散。多糖苷通过靶向细菌表面上称为LPS的化学物质来损害外膜。我们小组的工作表明，多聚淋巴素还通过靶向LPS损害了内膜，并且需要这种损害才能杀死细菌。但是，尚不清楚内膜中LPS靶向LPS的多牙我们的原因尚不清楚，并将在该提案中解决。在确定了多聚氧素如何杀性细菌之后，我们将研究多羟基耐药性如何保护细菌免受这类抗生素的影响，以及与耐药性相关的成本。从本文中，我们发现一种称为Murepavadin的实验性抗生素可以使细菌对抗酸性的抗酸性蛋白质（包括polymansys抗氧蛋白）的杀伤非常敏感。通过了解这种情况的发生方式，我们可以制定逆转多性多粘蛋白抗性的策略，该项目将提供有关多型多粘蛋白如何杀死细菌，多性层状耐药功能以及如何反转多性多粘蛋白抗性的洞察力。