Acinetobacter baumannii OxPhos inhibitors as selective anti-infective agents.
Acinetobacter baumannii OxPhos inhibitors as selective anti-infective agents.
复制标题
鲍曼不动杆菌 OxPhos 抑制剂作为选择性抗感染剂。
DOI：
10.1016/j.bmcl.2014.11.020
复制
发表时间：
2015
影响因子：
2.7
通讯作者：
Reitz,AllenB
中科院分区：
文献类型：
--
作者：
Rubin,Harvey;Selwood,Trevor;Yano,Takahiro;Weaver,DamianG;Loughran,HMarie;Costanzo,MichaelJ;Scott,RichardW;Wrobel,JayE;Freeman,KatieB;Reitz,AllenB
The Gram-negative bacterium Acinetobacterbaumanniiis an opportunistic pathogen in humans and infections are poorly treated by current therapy. Recent emergence of multi-drug resistant strains and the lack of new antibiotics demand an immediate action for development of new anti-Acinetobacter agents. To this end, oxidative phosphorylation (OxPhos) was identified as a novel target for drug discovery research. Consequently, a library of ∼10,000 compounds was screened using a membrane-based ATP synthesis assay. One hit identified was the 2-iminobenzimidazole1that inhibited the OxPhos ofA. baumanniiwith a modestly high selectivity against mitochondrial OxPhos, and displayed an MIC of 25 μM (17 μg/mL) against the pathogen. The 2-iminobenzimidazole1was found to inhibit the type 1 NADH–quinone oxidoreductase (NDH-1) ofA. baumanniiOxPhos by a biochemical approach. Among various derivatives that were synthesized to date, des-hydroxy analog5is among the most active with a relatively tight SAR requirement for the N′-aminoalkyl side chain. Analog5also showed less cytotoxicity against NIH3T3 and HepG2 mammalian cell lines, demonstrating the potential for this series of compounds as anti-Acinetobacteragents. Additional SAR development and target validation is underway.
