Targeting antibiotic resistance: the importance of genome segregation

细菌对抗生素的耐药性是世界范围内对人类健康的主要威胁。耐多药“超级细菌”的出现要么是基因组内突变的结果，要么是存在于可移动遗传元件(如质粒)上的耐药基因水平转移的结果。负责抗生素耐药性的低拷贝数质粒采用复杂的策略，以确保在细胞分裂时忠实地分配。这些质粒编码两种蛋白质，一种ATPase和一种DNA结合蛋白，它们组装成一个最低限度的DNA分离机器。这种蛋白质复合体与染色体相互作用，并将质粒驱动到特定的亚细胞地址。当这个系统发生故障时，质粒就会丢失，导致对抗生素敏感的细菌种群。我们的模型系统是一个多药耐药质粒，它在大肠杆菌中复制。该质粒编码两种蛋白质，这两种蛋白质形成一个复合体，负责在细胞中维持该质粒。我们提出了一个金星捕蝇器模型作为一种质粒分离的机制，该模型预测质粒被捕获在由其中一种蛋白质形成的三维笼状基质中。该项目将利用物理-生物界面的多学科前沿方法，在单分子水平上研究分离蛋白的相互作用和复杂组装的动力学。

Bacterial antibiotic resistance is a major threat to human health worldwide. The emergence of multidrug-resistant 'superbugs' results either from mutations within the genome or from the horizontal transfer of resistance genes present on mobile genetic elements such as plasmids. Low-copy number plasmids responsible for antibiotic resistance employ sophisticated strategies to ensure faithful distribution at cell division. These plasmids encode two proteins, an ATPase and a DNA-binding protein, which assemble into a minimalist DNA segregation machine. This protein complex interacts with the chromosome and drives the plasmids to defined subcellular addresses. When this systems malfunctions, the plasmid is lost, resulting in an antibiotic-sensitive bacterial population. Our model system is a multidrug resistant plasmid, which replicates in Escherichia coli. The plasmid encodes two proteins that form a complex responsible for maintaining the plasmid in the cell. We proposed a Venus flytrap model as a mechanism for plasmid segregation, which predicts that the plasmid is captured within a three-dimensional cage-like matrix formed by one of the proteins. This project will investigate the interaction of the segregation proteins and the dynamics of complex assembly at single-molecule level, using multidisciplinary cutting-edge approaches at the physics-biology interface.