Morphological profiling of tubercle bacilli identifies drug pathways of action
| Autor: | Xin Wang, Joel S. Freundlich, Trever C. Smith, Michaela C. Olson, Jonah Larkins-Ford, Ian W. Richardson, Bree B. Aldridge, Sophia Hu, Krista M. Pullen, D. Michael Ando, Morgan E. McNellis |
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| Rok vydání: | 2020 |
| Předmět: |
Drug
Bacilli Cell type media_common.quotation_subject Antitubercular Agents Computational biology Drug action high throughput Cell morphology Microbiology drug discovery Mycobacterium tuberculosis chemistry.chemical_compound Cell Wall Diarylquinolines media_common cell morphology Multidisciplinary biology Drug discovery Biological Sciences biology.organism_classification High-Throughput Screening Assays chemistry tuberculosis Bedaquiline Transcriptome Software |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| Popis: | Significance Tuberculosis is a leading cause of death in the world and requires treatment with an arduous multidrug regimen. Many new tuberculosis drugs are in development, and the drug development pipeline would benefit from more rapid methods to learn drug mechanism of action and off-target effects. Here we describe a high-throughput imaging method for rapidly classifying drugs into categories based on the primary and secondary mechanisms of cellular damage caused by different antibacterials called Morphological Evaluation and Understanding of Stress (MorphEUS). We anticipate that MorphEUS will assist in rapidly pinpointing pathway of action of antibacterials for tuberculosis and other bacterial infections. 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 Mycobacterium tuberculosis 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. |
| Databáze: | OpenAIRE |
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