Mechanistic and structural analysis of topo IV and gyrase and their targeting by antibacterial quinolones

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Topo IV and gyrase are enzymes that untangle bacterial chromosomes and are important targets of anti-infective drugs. Both enzymes make a DNA break (known as a 'gate') in one DNA molecule and pass a second DNA helix through the gate. Quinolone drugs kill bacteria by stabilizing the enzyme-opened gate. This project aims to understand how topo IV and gyrase mediate gate opening and closure, and how drugs interfere with these fundamental processes. The study builds on insights gained from our recent X-ray crystal structure that revealed how quinolones act at the topo IV-DNA gate. This structure provides a number of intriguing mechanistic hypotheses to be tested and paves the way for the design and evaluation of new inhibitors with novel modes of action that should minimize the emergence of drug resistance.