Melander Roberta J, Mattingly Anne E, Melander Christian
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, United States.
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, United States.
Methods Enzymol. 2022;665:153-176. doi: 10.1016/bs.mie.2021.11.005. Epub 2021 Dec 9.
The identification of antibiotic adjuvants, small molecules that potentiate the activity of conventional antibiotics, provides an orthogonal approach to the development of new antibiotics in the fight against drug resistant bacterial infections. Methods to identify novel adjuvants could potentially aid efforts to overcome the increasing prevalence of resistance and stave off the onset of a "post-antibiotic era." Phenotypic whole cell screens allow for the identification of hits with the necessary properties to access their biomolecular target, and may also facilitate the discovery of novel adjuvant targets. A phenotypic screening platform is outlined, in which a natural product library was explored for activity with antibiotics from several mechanistically distinct classes against clinically important bacterial species. General approaches to delineating the mechanism of action of hit compounds identified from phenotypic screens are described, followed by specific approaches to uncovering the mechanism of action of the colistin adjuvants identified from the natural product screen.
抗生素佐剂是一类能够增强传统抗生素活性的小分子，其鉴定为对抗耐药性细菌感染的新型抗生素开发提供了一种正交方法。鉴定新型佐剂的方法可能有助于克服耐药性日益普遍的问题，并延缓“后抗生素时代”的到来。表型全细胞筛选能够鉴定出具有必要特性以接近其生物分子靶点的命中物，还可能促进新型佐剂靶点的发现。本文概述了一个表型筛选平台，其中探索了一个天然产物库，以研究来自几个机制不同类别的抗生素对临床重要细菌物种的活性。描述了描绘从表型筛选中鉴定出的命中化合物作用机制的一般方法，随后介绍了揭示从天然产物筛选中鉴定出的黏菌素佐剂作用机制的具体方法。
