A natural product inspired fragment-based approach towards the development of novel anti-bacterial agents
A natural product inspired fragment-based approach towards the development of novel anti-bacterial agents
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DOI：
10.1039/c6md00229c
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发表时间：
2016-01-01
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影响因子：
--
通讯作者：
Searcey, Mark
中科院分区：
文献类型：
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作者：
Austin, Michael J.;Hearnshaw, Stephen J.;Searcey, Mark
发现具有新型作用模式的新型抗生素来对抗抗菌素耐药性（AMR）至关重要。天然产物simmocyclinone D8 （SD8）是一种有效的DNA回转酶抑制剂。它的双功能结构和新的作用模式为抗生素的开发提供了一个鼓舞人心的线索。在这里，我们描述了一种基于片段的原理证明方法，用于开发一类新的香豆素-喹诺酮类化合物。我们证明香豆素部分是杂交化合物观察到的抑制活性（IC50类似于3 μ M）所必需的，这部分是通过剪切dna中间体的稳定介导的。
The discovery of new antibiotics with novel modes of action to combat antimicrobial resistance (AMR) is of vital importance. The natural product simocyclinone D8 (SD8) is a potent inhibitor of DNA gyrase. Its bi-functional structure and novel mode of action serve as an inspiring lead for antibiotic development. Herein we describe a proof of principle fragment-based approach towards the development of a new class of coumarin-quinolone hybrids. We demonstrate that the coumarin moiety is required for the observed inhibitory activity (IC50 similar to 3 mu M) of the hybrid compound, which is in part mediated through stabilisation of a cleaved-DNA intermediate.