Understanding bacterial DNA gyrase for the development of novel antibiotics

DNA促旋酶是一种存在于所有细菌中的蛋白质，可以通过瞬时切割双螺旋将超螺旋引入DNA。这种反应的DNA断裂-重新结合步骤的中断可导致细菌中的致命损伤。这种机制特征，加上它在人类中的缺失，使其成为抗菌剂的一个非常成功的靶标。然而，许多问题仍然没有解决的链通过机制，特别是依赖于分子的动力学。来自晶体学和冷冻电镜的关于旋转酶的新结构信息的爆炸给了我们及时的机会来剖析机制，从而在这个关键的纳米机器上找到新的目标。通过使用从这样的结构的全原子模拟，我们的目标是解决这些问题，以期开发新的配体，可以破坏其催化活性。我们还将使用新的突破性AI算法（例如DeepChem）进行计算机筛选，以识别潜在的配体，这些算法已经彻底改变了该领域。候选药物将与Inspiralis合作进行实验测试。

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.