Morphological profiling of tubercle bacilli identifies drug pathways of action

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 deve...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 117; no. 31; pp. 18744 - 18753
Main Authors Smith, Trever C., Pullen, Krista M., Olson, Michaela C., McNellis, Morgan E., Richardson, Ian, Hu, Sophia, Larkins-Ford, Jonah, Wang, Xin, Freundlich, Joel S., Ando, D. Michael, Aldridge, Bree B.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 04.08.2020
Subjects
Antitubercular Agents - pharmacology
Bacilli
Biological Sciences
Cell Wall - drug effects
Cell walls
Classification
Damage
Diarylquinolines
Downstream effects
Drug Discovery - methods
High-Throughput Screening Assays
Morphology
Moxifloxacin
Mycobacterium tuberculosis - cytology
Mycobacterium tuberculosis - drug effects
Mycobacterium tuberculosis - metabolism
Software
Target recognition
Transcriptome - drug effects
Tuberculosis
cell morphology
drug discovery
high throughput
tuberculosis
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Summary: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.
Bibliography:1T.C.S. and K.M.P. contributed equally to this work.
Author contributions: T.C.S., K.M.P., J.L.-F., X.W., J.S.F., D.M.A., and B.B.A. designed research; T.C.S., K.M.P., and M.E.M. performed research; T.C.S., K.M.P., M.C.O., M.E.M., I.R., S.H., J.L.-F., X.W., J.S.F., and B.B.A. contributed new reagents/analytic tools; T.C.S., K.M.P., M.C.O., I.R., S.H., J.L.-F., X.W., J.S.F., D.M.A., and B.B.A. analyzed data; and T.C.S., K.M.P., M.C.O., M.E.M., X.W., J.S.F., and B.B.A. wrote the paper.
Edited by Babak Javid, Tsinghua University, Beijing, China, and accepted by Editorial Board Member Carl F. Nathan June 16, 2020 (received for review February 12, 2020)
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2002738117