Understanding bacterial DNA gyrase for the development of novel antibiotics

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DNA gyrase is a protein found in all bacteria that can introduce supercoils into DNA through transiently cutting the double helix. Interruption of the DNA breakage-reunion step of this reaction can lead to a lethal lesion in bacteria. This mechanistic feature, plus its absence from humans, has made it a highly-successful target for antibacterial agents. However, many questions remain unsolved concerning the strand-passage mechanism, which particularly relies on the dynamics of the molecule. The explosion of new structural information on gyrase from crystallography and cryo-EM give us the timely opportunity to dissect the mechanism and thus find new targets on this key nano-machine. By using all-atom simulations from such structures, we aim to address these questions with a view to developing novel ligands that can disrupt its catalytic activity. We will also perform in silico screening for identifying potential ligands using novel ground-breaking AI algorithms (for example DeepChem) that have revolutionized the field. The drug candidates will be tested experimentally in collaboration with Inspiralis.