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Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection
Published on: October 25, 2013
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Antibacterial mechanisms identified through structural systems pharmacology.
Roger L Chang1, Lei Xie, Philip E Bourne
1Department of Bioengineering, University of California San Diego, La Jolla, CA 92093-0412, USA. palsson@ucsd.edu.
BMC Systems Biology
|October 12, 2013
Summary
This study introduces a structural systems pharmacology framework to predict antibacterial compound activity in Escherichia coli. The approach accurately predicts known activities and uncovers novel mechanisms, aiding new antibacterial drug discovery.
Area of Science:
- Structural systems pharmacology
- Computational biology
- Drug discovery
Background:
- Structural systems pharmacology is an emerging discipline for predicting antibacterial compound effects.
- This study builds on prior work in structural prediction of ligand binding pockets and the genome-scale model of metabolism integrated with protein structures (GEM-PRO) for E. coli.
- The GEM-PRO model was expanded to structurally account for protein complexes in E. coli K12.
Purpose of the Study:
- To apply and expand a structural systems pharmacology framework for predicting antibacterial compound outcomes in E. coli K12.
- To validate the framework's predictive capabilities using known antibacterial compounds.
- To identify novel mechanisms of action and potential drug targets for antibacterial development.
Main Methods:
- Utilized a genome-scale model of metabolism integrated with protein structures (GEM-PRO) for E. coli.
- Applied structural prediction of ligand binding pockets on protein molecules.
- Validated the prediction framework with control compounds and investigated novel mechanisms for known antibacterials.
Main Results:
- The framework accurately predicted the antibacterial activity of fosfomycin, sulfathiazole, and trimethoprim, and correctly identified glucose as non-antibacterial.
- Previously uncharacterized mechanisms of action were predicted for compounds like (1-hydroxyheptane-1,1-diyl)bis(phosphonic acid) and cholesteryl oleate.
- Five candidate inhibitors were predicted for tryptophan synthase β subunit (TrpB), a target lacking known inhibitors. The GEM-PRO model was significantly expanded to include protein complex structures.
Conclusions:
- The structural systems pharmacology framework effectively predicts molecular mechanisms of antibacterial compounds.
- The study demonstrates a promising proof of principle for developing new antibacterials.
- The framework and its predictions are extensible to pathogenic E. coli and other bacterial pathogens.
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