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

洋葱伯克霍尔德菌复合体（Bcc）代表了一大批人类病原体，可引起包括囊性纤维化患者在内的免疫功能低下个体的肺部感染。由于对临床上广泛可用的抗生素具有很高的内在耐药性，基底细胞癌感染可能是致命的且难以治疗。因此，迫切需要确定新型抗微生物药物治疗Bcc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的生理过程中，我们最近发现Bcc细菌可以改变感染中的膜脂。因此，在感染期间，这些细菌对营养物质的可用性做出反应，产生含糖脂质来取代膜磷脂。参与这种所谓的膜脂重塑过程的一个关键基因是plcP。重要的是，该基因对于在昆虫感染模型以及人类和小鼠巨噬细胞模型中成功感染Bcc至关重要。因此，这种plcp介导的脂质重塑途径是未来开发治疗Bcc感染的新型抗生素的一个有希望的新药物靶点。利用我们的发现，我们建议使用分子和细胞微生物学、生物化学和“组学”工具的合成，系统地研究Bcc感染中营养物质、膜脂重塑和先天免疫的相互作用。该项目的研究结果有可能有助于开发治疗人类Bcc感染的新药物靶点。

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.