来自新出现的病原菌 Candida auris 的二叶酸减少酶的晶体结构
Tim Kirkman1, Alice Sketcher1, Vinicius de Morais Barroso2
1Department of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom.
Acta crystallographica. Section D, Structural biology
|July 10, 2023
概括
新的研究揭示了Candida auris二叶酸减少酶 (CauDHFR) 的晶体结构. 这些发现为开发新型抗真菌药物来对抗耐药的Candida auris病原体提供了基础.
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:
- 黄是一种日益严重的全球健康问题,原因是其高死亡率和对现有抗真菌治疗的耐药性.
- 对于Candida auris感染的治疗选择有限,需要开发新的治疗策略.
- 双叶酸还原酶 (DHFR) 是一种在Candida物种中验证的药物标,但其在C. auris中的结构仍然未被描述.
研究的目的:
- 为了确定Candida auris二叶酸减少酶 (CauDHFR) 酶的晶体结构.
- 为了研究该酶与已知的抗叶酸药物的相互作用.
- 提供结构和功能数据,以指导针对C. auris.的新抗真菌疗法的开发.
主要方法:
- 采用X射线晶体学,以获得CauDHFR的高分辨率结构,以apo,holo和三元复合形式.
- 进行了生物化学和生物物理分析,以评估酶抑制.
- 使用经典抗叶剂进行了抗真菌敏感性测试.
主要成果:
- 在近原子分辨率下确定了CauDHFR的晶体结构,包括阿波酶,全酶,以及与甲胺和环流的复合物.
- 初步测定表明了酶抑制率和对酵母生长的影响.
- 该研究提供了对CauDHFR及其与抗叶酸的相互作用的详细结构见解.
结论:
- 报告的CauDHFR的晶体结构为基于结构的药物设计提供了关键的基础.
- 这些发现为开发针对C. auris.中这种必不可少的酶的新型治疗剂铺平了道路.
- 这项研究为打击抗药性Candida auris感染带来的全球威胁提供了一个有希望的途径.
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