Morphological profiling of tubercle bacilli identifies drug pathways of action.

Proceedings of the National Academy of Sciences of the United States of America
Trever C SmithBree Aldridge

Abstract

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.

References

Mar 11, 1992·The American Review of Respiratory Disease·Y ZhangR J Wallace
Dec 1, 1995·Antimicrobial Agents and Chemotherapy·H F ChambersH Nikaido
Jan 24, 2003·Infection and Immunity·Steven I DurbachValerie Mizrahi
Apr 27, 2005·Journal of Bioinformatics and Computational Biology·Chris Ding, Hanchuan Peng
Oct 6, 2007·Biochemistry·Jean-Emmanuel Hugonnet, John S Blanchard
Mar 13, 2008·Proceedings of the National Academy of Sciences of the United States of America·Amit K Pandey, Christopher M Sassetti
Oct 27, 2009·Nature Reviews. Microbiology·Clifton E BarryDouglas Young
Oct 20, 2010·Antimicrobial Agents and Chemotherapy·John B BruningJames C Sacchettini
Sep 21, 2013·Proceedings of the National Academy of Sciences of the United States of America·Poochit NonejuieJoe Pogliano
Feb 26, 2014·BMC Bioinformatics·Pablo A JaskowiakIvan G Costa
Feb 11, 2015·Protein and Peptide Letters·Manju LataKrishnamurthy Venkatesan
Jun 25, 2015·Microbiology Spectrum·Martin S PavelkaDean C Crick
Dec 1, 2015·PLoS Computational Biology·Shuyi MaNathan D Price
Jul 1, 2016·Proceedings of the National Academy of Sciences of the United States of America·Kirill RichardsonBree B Aldridge
Jul 20, 2016·Proceedings of the National Academy of Sciences of the United States of America·Thulasi WarrierCarl F Nathan
Aug 31, 2016·Antimicrobial Agents and Chemotherapy·Krupa NaranDigby F Warner
Aug 31, 2016·Nature Microbiology·Adrien DucretYves V Brun
Jan 17, 2017·Trends in Microbiology·Heleen Van Acker, Tom Coenye
Feb 25, 2017·Microbiology Spectrum·Ben Gold, Carl Nathan
May 23, 2017·Nature Microbiology·Hyungjin EohKyu Y Rhee
Jun 9, 2017·Nature Communications·Tingying PengNassir Navab
Jun 18, 2017·Trends in Microbiology·Divya Awasthi, Joel S Freundlich
Sep 1, 2017·Nature Methods·Juan C CaicedoAnne E Carpenter
Feb 22, 2018·Antimicrobial Agents and Chemotherapy·Chao ChenVéronique Dartois
Apr 25, 2018·Nature Reviews. Microbiology·Sabine EhrtKyu Y Rhee
May 15, 2018·Frontiers in Cellular and Infection Microbiology·H M Adnan HameedTianyu Zhang
Aug 31, 2018·Frontiers in Microbiology·Annanya Shetty, Thomas Dick
Dec 12, 2018·The Journal of Biological Chemistry·Bei Shi LeeKevin Pethe
Dec 12, 2018·Nature Biotechnology·Etienne BechtEvan W Newell
Dec 13, 2018·MBio·Kenan C MurphyChristopher M Sassetti

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Citations

Oct 23, 2020·Nature·Neil Savage
Jun 5, 2021·RSC Medicinal Chemistry·Katherine A Abrahams, Gurdyal S Besra
Jul 3, 2021·Annals of the New York Academy of Sciences·Meilin ZhuPaul C Blainey
Aug 20, 2020·Journal of the American Chemical Society·Tingting DaiJianghong Rao

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Datasets Mentioned

BETA
GSE126718
GSE43749
GSE71200
GSE1642

Methods Mentioned

BETA
PCA
X-ray
phase contrast microscopy
fluorescence microscopy
Feature Extraction
environmental stress

Software Mentioned

R packages
cKNN
ORBIT
pheatmap
MorphEUS
ImageJ
R
MicrobeJ
Morphological Evaluation and Understanding of Stress ( MorphEUS )
MATLAB

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