The Rational Design, Synthesis, and Antimicrobial Properties of Thiophene Derivatives That Inhibit Bacterial Histidine Kinases.
The Rational Design, Synthesis, and Antimicrobial Properties of Thiophene Derivatives That Inhibit Bacterial Histidine Kinases.
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DOI：
10.1021/acs.jmedchem.6b00580
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发表时间：
2016-10-13
影响因子：
7.3
通讯作者：
Meffre P
中科院分区：
文献类型：
--
作者：
Boibessot T;Zschiedrich CP;Lebeau A;Bénimèlis D;Dunyach-Rémy C;Lavigne JP;Szurmant H;Benfodda Z;Meffre P
多重耐药细菌的出现强调了对靶向独特细胞过程的新型抗菌化合物的迫切需求。双组分信号转导系统（TCSs）通常被细菌用于将环境刺激耦合到适应性反应，在哺乳动物中不存在，并且嵌入各种致病途径中。为了减弱这些信号通路，我们的目标是通过关注TCS信号转导组氨酸激酶（HK）高度保守的三磷酸腺苷（ATP）结合结构域。我们使用基于结构的药物设计策略来鉴定细菌HK的新抑制剂。因此，设计了配体，得到了一系列噻吩衍生物。合成这些化合物并在体外评价其对细菌HK的作用。我们确定了八个化合物对这些蛋白质具有显着的抑制活性，其中两个表现出广谱抗菌活性。还将化合物评价为佐剂抗性细菌。发现一种化合物可以恢复这些细菌对相应抗生素的敏感性。
The emergence of multi-drug-resistant bacteria emphasizes the urgent need for novel antibacterial compounds targeting unique cellular processes. Two-component signal transduction systems (TCSs) are commonly used by bacteria to couple environmental stimuli to adaptive responses, are absent in mammals, and are embedded in various pathogenic pathways. To attenuate these signaling pathways, we aimed to target the TCS signal transducer histidine kinase (HK) by focusing on their highly conserved adenosine triphosphate (ATP)-binding domain. We used a structure-based drug design strategy to identify new inhibitors of bacterial HKs. Thus, ligands were designed, leading to a series of thiophene derivatives. These compounds were synthesized and evaluated in vitro against bacterial HKs. We identified eight compounds with significant inhibitory activities against these proteins, two of which exhibited broad-spectrum antimicrobial activity. The compounds were also evaluated as adjuvant resistant bacteria. One compound was found to restore the sensivity of these bacteria to the respective antibiotics.
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