Bacterial lipocalins: Novel role in bacterial protection against antibiotic-induced membrane lipid peroxidation

细菌脂质运载蛋白：在防止抗生素诱导的膜脂过氧化的细菌保护中的新作用

基本信息

批准号：
BB/S006281/1
负责人：
Miguel Valvano
金额：
$ 56.46万
依托单位：
Queen's University Belfast
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FS006281%2F1
关键词：
Bacterial lipocalins Novel role bacterial

项目摘要

Research on antibiotic action and resistance has helped elucidate fundamental biochemical and regulatory pathways in bacteria and fungi operating within the microbial cells. However, whether bacteria produce molecules that interfere with antibiotics before they reach cells has been overlooked. We discovered a previously unrecognized mode of bacterial antibiotic resistance operating in the extracellular space that depends on molecules produced and released by bacteria in response to sublethal antibiotic concentrations. This adaptive mechanism protects less resistant bacterial cells of the same or different species from killing by antibiotics. The molecules involved are putrescine, a polyamine, and secreted lipocalin proteins, which are highly conserved in bacteria. We also discovered that lipocalins are part of a previously ignored mechanism to protect cell membranes from lipid peroxidation. Peroxidation occurs as a consequence of environmental stress including bacterial exposure to near-lethal antibiotic concentrations, cold, and inflammation. Lipid peroxidation ends up with the destruction of membrane lipids and their conversion into highly toxic forms which in turn can oxidise and destroy cellular proteins and the genetic material. This proposal is on fundamental microbiology research combining molecular microbiology, biochemistry, and infection models to elucidate the role of a conserved family of bacterial lipocalins in bacterial cell physiology and antibiotic resistance. Our long-term goals are to establish the function of lipocalins by elucidating their mechanism and physiological roles in bacterial cells, and to utilise this information to gain proof of principle that new molecules can be designed to help prevent extracellular bacterial scavenging of antibiotics, and more importantly accelerate peroxidation leading to bacterial death, thus providing a potentially new solution to combat antibiotic resistance.

抗生素作用和耐药性的研究有助于阐明微生物细胞中细菌和真菌的基本生化和调节途径。但是，细菌是否产生在进入细胞之前会干扰抗生素的分子已被忽略。我们在细胞外空间中发现了一种先前无法识别的细菌抗生素耐药性模式，该模式取决于细菌响应于环的抗生素浓度而产生和释放的分子。这种自适应机制可保护相同或不同物种的耐药细胞不受抗生素杀死。所涉及的分子是腐霉菌，一种多胺和分泌的Lipocalin蛋白，它们在细菌中高度保守。我们还发现，脂质蛋白是保护细胞膜免受脂质过氧化的一种先前忽略的机制的一部分。过氧化是由于环境应激而发生的，包括细菌暴露于接近致死的抗生素浓度，冷和炎症。脂质的过氧化作用最终是膜脂质的破坏及其转化为剧毒形式，进而可以氧化并破坏细胞蛋白和遗传物质。该建议基于结合分子微生物学，生物化学和感染模型的基本微生物研究，以阐明保守的细菌脂蛋白家族在细菌细胞生理学和抗生素耐药性中的作用。我们的长期目标是通过阐明其在细菌细胞中的机制和生理作用来建立脂质蛋白的功能，并利用这些信息来获得原理证明，即可以设计新的分子来帮助防止细胞外的细菌清除抗生素，并更重要的是可抗药地抗药性，从而使饲养能够抗细菌，从而使新的抗生素具有新的作用。