Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections
Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections
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发现新型吡啶酮结合单磺内酰胺作为治疗多重耐药革兰氏阴性菌感染的强效广谱抗生素
DOI：
10.1021/acs.jmedchem.6b01261
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发表时间：
2017
影响因子：
7.3
通讯作者：
Yang Yushe
中科院分区：
文献类型：
--
作者：
Tan Liang;Tao Yunliang;Wang Ting;Zou Feng;Zhang Shuhua;Kou Qunhuan;Niu Ao;Chen Qian;Chu Wenjing;Chen Xiaoyan;Wang Haidong;Yang Yushe
将铁载体与抗生素结合是克服革兰氏阴性病原体渗透性介导的耐药性的一种有前途的策略。在BAL30072结构的基础上，设计并合成了新型吡啶酮共轭单磺内酰胺，在1,3-二羟基吡啶-4(1H)-酮和氨基噻唑肟之间的亚甲基连接基上掺入了不同的取代基。构效关系研究表明，多种取代基均具有耐受性，其中异丙基（化合物12c）和甲硫甲基（化合物16a）对多重耐药（MDR）革兰氏阴性病原体表现出最佳功效。此外，化合物12c在体外人血浆蛋白结合测试中表现出良好的游离分数率，以及低清除率和有利的体内血浆暴露。在MDRK肺炎杆菌的小鼠全身感染模型中，化合物12c显示的ED50为10.20mg/kg。综上所述，结果表明化合物 12 是治疗由 MDR 革兰氏阴性病原体引起的严重感染的有前途的候选药物。
Conjugating a siderophore to an antibiotic is a promising strategy to overcome the permeability-mediated resistance of Gram-negative pathogens. On the basis of the structure of BAL30072, novel pyridone-conjugated monosulfactams incorporating diverse substituents into the methylene linker between the 1,3-dihydroxypyridin-4(1H)-one and the aminothiazole oxime were designed and synthesized. Structure–activity relationship studies revealed that a variety of substituents were tolerated, with isopropyl (compound12c) and methylthiomethyl (compound16a) showing the best efficacy against multidrug-resistant (MDR) Gram-negative pathogens. In addition, compound12cexhibits a good free fraction rate in an in vitro human plasma protein binding test, along with a low clearance and favorable plasma exposure in vivo. In a murine systemic infection model with MDRKlebsiella pneumoniae, compound12cshows an ED50of 10.20 mg/kg. Taken together, the results indicate that compound12cis a promising drug candidate for the treatment of serious infections caused by MDR Gram-negative pathogens.