Targeting antibiotic resistance: the importance of genome segregation

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.