Cossar Peter J, Abdel-Hamid Mohammed K, Ma Cong, Sakoff Jennette A, Trinh Trieu N, Gordon Christopher P, Lewis Peter J, McCluskey Adam
Chemistry, School of Environmental & Life Sciences and Biology, Centre for Chemical Biology and Clinical Pharmacology, School of Environmental & Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
ACS Omega. 2017 Jul 31;2(7):3839-3857. doi: 10.1021/acsomega.7b00273. Epub 2017 Jul 25.
The NusB-NusE protein-protein interaction (PPI) is critical to the formation of stable antitermination complexes required for stable RNA transcription in all bacteria. This PPI is an emerging antibacterial drug target. Pharmacophore-based screening of the mini-Maybridge compound library (56 000 molecules) identified ,'-[1,4-butanediylbis(oxy-4,1-phenylene)]bis(-ethyl)urea as a lead of interest. Competitive enzyme-linked immunosorbent assay screening validated as a 20 μM potent inhibitor of NusB-NusE. Four focused compound libraries based on , comprising 34 compounds in total were designed, synthesized, and evaluated as NusB-NusE PPI inhibitors. Ten analogues displayed NusB-NusE PPI inhibition ≥50% at 25 μM concentration in vitro. In contrast to representative Gram-negative and Gram-positive species, these analogues showed up to 100% growth inhibition at 200 μM. 2-(()-4-((()-4-(4-(()-(Carbamimidoylimino)methyl)phenoxy)but-2-en-1-yl)oxy)benzylidene)hydrazine-1-carboximidamide showed excellent activity against important pathogens. With minimum inhibitory concentration values of ≤3 μg/mL for Gram-positive and methicillin-resistant and ≤51 μg/mL for Gram-negative and , is a potent lead for a novel antibacterial target. Epifluorescence studies in live bacteria were consistent with , inhibiting the NusB-NusE PPI as proposed.
NusB-NusE蛋白-蛋白相互作用（PPI）对于所有细菌中稳定RNA转录所需的稳定抗终止复合物的形成至关重要。这种PPI是一个新兴的抗菌药物靶点。基于药效团对迷你美桥化合物库（56000个分子）进行筛选，确定'-[1,4-丁二醇双（氧基-4,1-亚苯基）]双（-乙基）脲为感兴趣的先导化合物。竞争性酶联免疫吸附测定筛选验证其为NusB-NusE的20μM有效抑制剂。设计、合成并评估了基于该先导化合物的四个聚焦化合物库，总共包含34种化合物作为NusB-NusE PPI抑制剂。10种类似物在25μM浓度下体外显示出对NusB-NusE PPI的抑制率≥50%。与代表性革兰氏阴性菌和革兰氏阳性菌不同，这些类似物在200μM时显示出高达100%的生长抑制率。2-（（）-4-（（）-4-（4-（（）-（氨基甲脒基亚氨基）甲基）苯氧基）丁-2-烯-1-基）氧基）亚苄基）肼-1-甲脒酰胺对重要病原体显示出优异活性。对于革兰氏阳性菌和耐甲氧西林菌，其最低抑菌浓度值≤3μg/mL，对于革兰氏阴性菌和，其最低抑菌浓度值≤51μg/mL，是一种针对新型抗菌靶点的有效先导化合物。在活细菌中进行落射荧光研究，结果与该化合物如所提出的那样抑制NusB-NusE PPI一致。
