How does membrane lipid remodelling enable intracellular survival of B. cenocepacia?

膜脂重塑如何使新洋葱伯克霍尔德氏菌在细胞内存活？

• 批准号: BB/X01651X/1
• 负责人: Yin Chen
• 金额: $ 64.87万
• 依托单位: University of Birmingham
• 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%2FX01651X%2F1
• 关键词: How; does; membrane; lipid; remodelling

The Burkholderia cepacia complex (Bcc) represents a large group of human pathogens which cause lung infection in immunocompromised individuals including cystic fibrosis patients. Bcc infections can be lethal and difficult to treat due to high intrinsic resistance to a wide range of clinically available antibiotics. As such, there is an urgent need to identify new targets for novel antimicrobial drugs for Bcc. In our continued effort to better understand the physiology of bacterial membrane lipids in bacterial pathogens, we have recently found that Bcc bacteria can change membrane lipids in infection. Thus, in response to nutrient availability during infection, these bacteria produce sugar-containing lipids to replace membrane phospholipids. A key gene involved in this so-called membrane lipid remodelling process is plcP. Importantly, this gene is essential for successful infection of Bcc in an insect infection model as well as human and murine macrophage models. This PlcP-mediated lipid remodelling pathway is therefore a promising new drug target for future development of novel antibiotics for treating Bcc infection. Capitalising on our discovery, we propose to systematically investigate the interplay of nutrients, membrane lipid remodelling and innate immunity in Bcc infection, using a synthesis of molecular and cellular microbiology, biochemistry and 'omics' tools. The results of this project have the potential for help developing new drug targets for treating Bcc infection in human.

洋葱伯克霍尔德氏菌复合体（Bcc）代表一大组人类病原体，其在免疫功能低下的个体（包括囊性纤维化患者）中引起肺部感染。由于对广泛的临床可用抗生素的高内在耐药性，BCC感染可能是致命的并且难以治疗。因此，迫切需要确定用于BCC的新型抗微生物药物的新靶点。在我们继续努力更好地了解细菌病原体中细菌膜脂质的生理学过程中，我们最近发现Bcc细菌可以在感染中改变膜脂质。因此，在感染过程中，为了响应营养的可用性，这些细菌产生含糖脂质来取代膜磷脂。参与这种所谓的膜脂质重塑过程的关键基因是plcP。重要的是，该基因对于在昆虫感染模型以及人和鼠巨噬细胞模型中成功感染Bcc是必需的。因此，这种PlcP介导的脂质重塑途径是未来开发用于治疗BCC感染的新型抗生素的有希望的新药靶点。利用我们的发现，我们建议系统地研究营养物质，膜脂质重塑和先天免疫在BCC感染中的相互作用，使用分子和细胞微生物学，生物化学和“组学”工具的合成。该项目的结果有可能帮助开发治疗人类BCC感染的新药物靶点。