一个新型抗菌剂类别的IIA型拓酶抑制
Benjamin D Bax1, Pan F Chan, Drake S Eggleston
1Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK. benjamin.d.bax@gsk.com
Nature
|August 6, 2010
概括
一种新的广谱抗菌剂向金黄色葡萄球菌的DNA回转酶,提供一种新的抑制机制来对抗抗药性. 这项结构性研究为开发下一代抗生素对抗必需的细菌酶提供了基础.
科学领域:
- 微生物学 微生物学
- 结构生物学 结构生物学
- 药物发现 药物发现 药物发现
背景情况:
- 基因组学已经确定了必不可少的细菌基因,但由于越来越多的抗药性,缺乏可持续的抗菌药物线索.
- IIA型拓酶是重要的抗菌和抗癌药物标,但对它们的药物相互作用的详细结构理解是有限的.
研究的目的:
- 确定与新型抗菌剂复合的Staphylococcus aureus DNA 旋转酶的晶体结构.
- 阐明这种新类抑制剂的作用机制及其克服现有耐药性的潜力.
主要方法:
- 采用X射线晶体学,获得与Staphylococcus aureusDNA旋转酶和DNA结合的抑制剂的2.1 Å分辨率结构.
- 结构分析的重点是抑制剂与酶和DNA的相互作用,以及其接近活性和药物结合部位.
主要成果:
- 发现了一种新型的,广泛的抗菌剂通过一种独特的机制来抑制 Staphylococcus aureus DNA 旋转酶.
- 抑制剂在GyrA二聚体接口上桥接DNA和一个短暂的口袋,与诺基诺结合部位不同.
- 该结构揭示了准备用于DNA裂变的活性部位,该部位与酸附近的金属离子相结合,这表明了功能抑制模式.
结论:
- 这项研究为一种针对IIA型多酶的新型抗菌剂提供了第一个结构基础.
- 这些发现为基于结构的药物设计提供了一个平台,以开发针对耐药细菌有效的新型抗生素.
- 了解这种新的抑制模式对于应对细菌感染中多药耐药性的挑战至关重要.
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