Structural and Functional Studies of the β2-Sliding Clamp from Pathogenic Bacteria

The introduction of antibiotics in medicine revolutionised the treatment of common bacterial infections. However, bacteria have overcome the obstacles imposed by these compounds via several mechanisms. As a consequence, they are rapidly becoming resistant and we are now entering a post-antibiotic era, whereby all clinically used antibiotics will soon become obsolete. A group of pathogens, known as the ESKAPE pathogens, have been identified as those that give rise to the most infections in hospitals and effectively “escape” the effects of antibacterial drugs. Patients that are immunocompromised and in the intensive care units are most at risk. There is now a dire need for new antibiotics with unexplored mechanisms of action. The process of bacterial DNA replication is a vital function for bacterial survival that has many unexploited targets for new antibiotics. One such target is the bacterial !2- sliding clamp. This is a toroid protein that encircles DNA, and slides along the DNA during the replication and repair processes. It is a protein-protein interaction hub that acts as a mobile tether for polymerases to synthesise the nascent complementary DNA strands prior to cell division. Without the DNA replicated, bacteria are unable to divide and cannot propagate.