Department of Biological Chemistry, John Innes Centre, Colney, Norwich NR4 7UH, UK.
Science. 2009 Dec 4;326(5958):1415-8. doi: 10.1126/science.1179123.
Simocyclinones are bifunctional antibiotics that inhibit bacterial DNA gyrase by preventing DNA binding to the enzyme. We report the crystal structure of the complex formed between the N-terminal domain of the Escherichia coli gyrase A subunit and simocyclinone D8, revealing two binding pockets that separately accommodate the aminocoumarin and polyketide moieties of the antibiotic. These are close to, but distinct from, the quinolone-binding site, consistent with our observations that several mutations in this region confer resistance to both agents. Biochemical studies show that the individual moieties of simocyclinone D8 are comparatively weak inhibitors of gyrase relative to the parent compound, but their combination generates a more potent inhibitor. Our results should facilitate the design of drug molecules that target these unexploited binding pockets.
西蒙菌素酮是一种双功能抗生素，通过阻止 DNA 与酶结合来抑制细菌 DNA 回旋酶。我们报告了大肠杆菌 A 亚基拓扑异构酶与西蒙菌素酮 D8 形成的复合物的晶体结构，揭示了两个分别容纳抗生素的氨基香豆素和聚酮部分的结合口袋。这些口袋靠近但不同于喹诺酮结合位点，与我们的观察结果一致，即该区域的几个突变赋予了两种药物的抗性。生化研究表明，西蒙菌素酮 D8 的各个部分相对于母体化合物而言，对回旋酶的抑制作用较弱，但它们的组合产生了更有效的抑制剂。我们的结果应该有助于设计靶向这些未开发的结合口袋的药物分子。
