A robust platform for chemical genomics in bacterial systems

Molecular Biology of the Cell
Shawn FrenchEric D Brown

Abstract

While genetic perturbation has been the conventional route to probing bacterial systems, small molecules are showing great promise as probes for cellular complexity. Indeed, systematic investigations of chemical-genetic interactions can provide new insights into cell networks and are often starting points for understanding the mechanism of action of novel chemical probes. We have developed a robust and sensitive platform for chemical-genomic investigations in bacteria. The approach monitors colony volume kinetically using transmissive scanning measurements, enabling acquisition of growth rates and conventional endpoint measurements. We found that chemical-genomic profiles were highly sensitive to concentration, necessitating careful selection of compound concentrations. Roughly 20,000,000 data points were collected for 15 different antibiotics. While 1052 chemical-genetic interactions were identified using the conventional endpoint biomass approach, adding interactions in growth rate resulted in 1564 interactions, a 50-200% increase depending on the drug, with many genes uncharacterized or poorly annotated. The chemical-genetic interaction maps generated from these data reveal common genes likely involved in multidrug resistanc...Continue Reading

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Citations

Oct 22, 2016·Trends in Microbiology·Gerard D Wright
Sep 1, 2018·Molecular Biology and Evolution·Adam C PalmerRoy Kishony
Jul 10, 2019·Journal of Bacteriology·Darren J ParkerGene-Wei Li
Jan 27, 2019·Nature Reviews. Microbiology·Mike Tyers, Gerard D Wright
Oct 27, 2017·FEMS Microbiology Reviews·Kristina Klobucar, Eric D Brown
Apr 1, 2021·Accounts of Chemical Research·Maya A FarhaEric D Brown
Aug 25, 2020·ACS Combinatorial Science·Wei-Chieh ChengLee-Chiang Lo

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Methods Mentioned

BETA
gene knockout
chemical treatment

Software Mentioned

Excel
grofit
ImageJ
BioLayout3D
rPython
parallel
Pathway Tools
R
doParallel
Linux

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