Recreating the specific colicin N–Ra-LPS interaction in a model bacterial outer membrane

The Gram negative bacterial outer membrane protects the bacterium from external toxins such as antibiotics. This is partially responsible for Gram negative bacteria becoming the greatest emerging source of antibiotic resistance. The outer membrane is itself the target of some antibacterial agents such as polymixins but even these are subject to resistance mechanisms. We recently discovered that another antibacterial protein, colicin N, binds to the outer membrane lipid in a novel way that centres on the core oligosaccharide rather than the anionic phosphate groups targeted by the polymyxin family. In a recent paper we showed the importance of electrostatics in this binding and revealed that specific binding needed faults in the outer membrane model which expose the binding site. In this project we hope to define how exposure of the sugars allows for specific membrane binding.

革兰氏阴性菌（Gram negative bacteria）的外膜可保护菌体免受抗生素等外源毒素的侵袭。这也是革兰氏阴性菌成为抗生素耐药性最主要新兴来源的部分诱因。该外膜本身亦是多粘菌素类（polymixins）等部分抗菌剂的作用靶点，但即便此类抗菌剂也难逃耐药机制的影响。我们近期发现，另一类抗菌蛋白——大肠杆菌素N（colicin N）以全新方式结合外膜脂质：其结合位点聚焦于核心寡糖（core oligosaccharide），而非多粘菌素家族（polymyxin family）所靶向的阴离子磷酸基团（anionic phosphate groups）。在近期发表的论文中，我们阐明了静电作用（electrostatics）在该结合过程中的重要性，并揭示出特异性结合需要外膜模型中存在可暴露结合位点的结构缺陷。本项目旨在明确糖类暴露如何促成特异性膜结合。