Morphological profiling of tubercle bacilli identifies drug pathways of action
Trever C. Smith, Krista M. Pullen, Michaela C. Olson, Morgan E. McNellis, Ian Richardson, Sophia Hu, Jonah Larkins‐Ford, Xin Wang, Joel S. Freundlich, D. Michael Ando, Bree B. Aldridge
Abstract
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.