Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111.
Center for Integrated Management of Antimicrobial Resistance (CIMAR), Tufts University, Boston, MA 02111.
Proc Natl Acad Sci U S A. 2020 Aug 4;117(31):18744-18753. doi: 10.1073/pnas.2002738117. Epub 2020 Jul 17.
Morphological profiling is a method to classify target pathways of antibacterials based on how bacteria respond to treatment through changes to cellular shape and spatial organization. Here we utilized the cell-to-cell variation in morphological features of bacilli to develop a rapid profiling platform called Morphological Evaluation and Understanding of Stress (MorphEUS). MorphEUS classified 94% of tested drugs correctly into broad categories according to modes of action previously identified in the literature. In the other 6%, MorphEUS pointed to key off-target activities. We observed cell wall damage induced by bedaquiline and moxifloxacin through secondary effects downstream from their main target pathways. We implemented MorphEUS to correctly classify three compounds in a blinded study and identified an off-target effect for one compound that was not readily apparent in previous studies. We anticipate that the ability of MorphEUS to rapidly identify pathways of drug action and the proximal cause of cellular damage in tubercle bacilli will make it applicable to other pathogens and cell types where morphological responses are subtle and heterogeneous.
形态分析是一种根据细菌在治疗过程中通过细胞形态和空间组织的变化来对抗菌药物靶途径进行分类的方法。在这里，我们利用芽孢杆菌形态特征的细胞间差异，开发了一种称为形态评估和应激理解（MorphEUS）的快速分析平台。MorphEUS 根据文献中先前确定的作用模式，正确地将 94%的测试药物分类为广泛的类别。在其余的 6%中，MorphEUS 指出了关键的脱靶活性。我们通过主要靶途径下游的次级效应观察到了贝达喹啉和莫西沙星引起的细胞壁损伤。我们通过一项盲法研究实施了 MorphEUS，正确地对三种化合物进行了分类，并确定了一种在先前研究中不明显的化合物的脱靶效应。我们预计，MorphEUS 能够快速识别药物作用途径和结核分枝杆菌细胞损伤的近端原因的能力，将使其适用于其他形态反应细微和异质的病原体和细胞类型。
