Lim Andrew S T, Vincent Isabel M, Barrett Michael P, Gilbert Ian H
Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, U.K.
Glasgow Polyomics, University of Glasgow, Wolfson Wohl Cancer Research Centre, Garscube Campus, Bearsden G61 1QH, U.K.
ACS Omega. 2019 Nov 4;4(21):19199-19215. doi: 10.1021/acsomega.9b02507. eCollection 2019 Nov 19.
The global prevalence of antibacterial resistance requires new antibacterial drugs with novel chemical scaffolds and modes of action. It is also vital to design compounds with optimal physicochemical properties to permeate the bacterial cell envelope. We described an approach of combining and integrating whole cell screening and metabolomics into early antibacterial drug discovery using a library of small polar compounds. Whole cell screening of a diverse library of small polar compounds against gave compound . Hit expansion was carried out to determine structure-activity relationships. A selection of compounds from this series, together with other screened active compounds, was subjected to an initial metabolomics study to provide a metabolic fingerprint of the mode of action. It was found that compound and its analogues have a different mode of action from some of the known antibacterial compounds tested. This early study highlighted the potential of whole cell screening and metabolomics in early antibacterial drug discovery. Future works will require improving potency and performing orthogonal studies to confirm the modes of action.
全球抗菌药物耐药性的普遍存在需要具有新型化学骨架和作用方式的新型抗菌药物。设计具有最佳物理化学性质的化合物以渗透细菌细胞壁也至关重要。我们描述了一种将全细胞筛选和代谢组学结合并整合到早期抗菌药物发现中的方法，该方法使用了一个小极性化合物库。针对不同的小极性化合物库进行全细胞筛选得到了化合物 。进行命中物扩展以确定构效关系。从该系列中选择的化合物，以及其他筛选出的活性化合物，进行了初步代谢组学研究，以提供作用方式的代谢指纹图谱。发现化合物 及其类似物与一些测试的已知抗菌化合物具有不同的作用方式。这项早期研究突出了全细胞筛选和代谢组学在早期抗菌药物发现中的潜力。未来的工作将需要提高效力并进行正交研究以确认作用方式。
