Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis
Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis
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DOI：
10.1038/nchembio706
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发表时间：
2005-06-01
影响因子：
14.8
通讯作者：
Quadri, LEN
中科院分区：
文献类型：
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作者：
Ferreras, JA;Ryu, JS;Quadri, LEN
结核分枝杆菌和鼠疫耶尔森菌分别是结核病和鼠疫的病原体，是对全球公共卫生造成严重持续影响的病原体（1，2），并可能用作生物恐怖主义的病原体（3）。两种病原体都具有基于铁载体的铁获取系统，铁载体分泌具有极高Fe 3+亲和力的铁螯合化合物（4，5）。一些证据表明，铁载体在人类宿主内的细菌铁获取中具有关键作用（6-9），其中游离铁浓度远低于细菌生长和毒力所需的浓度（10）。因此，铁载体生物合成是开发治疗结核病和鼠疫的新抗生素的一个有吸引力的靶点（2，5，8，11）。特别是，这些药物，单独或作为联合治疗的一部分，可以提供一个有价值的新的防线，对难治性多重耐药感染。在这里，我们报告的设计，合成和生物学评价的机制为基础的抑制剂的结构域水杨酸酶所需的铁载体生物合成的M。结核和Y.鼠疫这种新抗生素能抑制嗜铁细胞的生物合成和生长。结核和Y.在铁限制条件下的鼠疫。
Mycobacterium tuberculosis and Yersinia pestis, the causative agents of tuberculosis and plague, respectively, are pathogens with serious ongoing impact on global public health(1,2) and potential use as agents of bioterrorism(3). Both pathogens have iron acquisition systems based on siderophores, secreted iron-chelating compounds with extremely high Fe3+ affinity(4,5). Several lines of evidence suggest that siderophores have a critical role in bacterial iron acquisition inside the human host(6-9), where the free iron concentration is well below that required for bacterial growth and virulence(10). Thus, siderophore biosynthesis is an attractive target in the development of new antibiotics to treat tuberculosis and plague(2,5,8,11). In particular, such drugs, alone or as part of combination therapies, could provide a valuable new line of defense against intractable multiple-drug-resistant infections. Here, we report the design, synthesis and biological evaluation of a mechanism-based inhibitor of domain salicylation enzymes required for siderophore biosynthesis in M. tuberculosis and Y. pestis. This new antibiotic inhibits siderophore biosynthesis and growth of M. tuberculosis and Y. pestis under iron-limiting conditions.