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

对抗生素作用和耐药性的研究有助于阐明细菌和真菌在微生物细胞内运行的基本生化和调控途径。然而，细菌是否会在到达细胞之前产生干扰抗生素的分子，这一点一直被忽视。我们发现了一种以前未知的细菌抗生素耐药性模式，这种模式在细胞外空间工作，依赖于细菌产生和释放的分子对亚致命抗生素浓度的反应。这种适应机制保护同种或不同种的抗药性较低的细菌细胞不被抗生素杀死。涉及的分子是腐胺，一种多胺，以及分泌的Lipocalin蛋白，它们在细菌中高度保守。我们还发现，Lipocalins是以前被忽视的保护细胞膜免受脂质过氧化的机制的一部分。过氧化是环境压力的结果，包括细菌暴露在接近致命的抗生素浓度下，寒冷和炎症。脂质过氧化最终导致膜脂的破坏，并将其转化为剧毒的形式，进而氧化和破坏细胞蛋白质和遗传物质。这项建议是基于基础微生物学研究，结合分子微生物学、生物化学和感染模型来阐明一个保守的细菌Lipocalin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它们在细菌细胞中的机制和生理作用来确定Lipocalins的功能，并利用这些信息来获得原理证据，即可以设计新的分子来帮助防止细胞外细菌清除抗生素，更重要的是加速导致细菌死亡的过氧化，从而提供一种潜在的新的解决方案来对抗抗生素耐药性。

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.