Antibacterial mechanisms identified through structural systems pharmacology

BMC Systems Biology

Bernhard O Palsson¹  Philip E Bourne³  Lei Xie²  Roger L Chang⁴ 

[1] Department of Bioengineering, University of California San Diego, La Jolla, CA 92093-0412, USA;The Graduate Center, The City University of New York, New York, NY 10065, USA;San Diego Supercomputer Center, University of California San Diego, La Jolla, CA USA;Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA

关键词: Escherichia coli;    Ligand binding;    Metabolic model;    Antibacterial;    Structural systems pharmacology;   

Others  :  1142067
DOI  :  10.1186/1752-0509-7-102

 received in 2013-07-02, accepted in 2013-10-07,  发布年份 2013

【 摘 要 】

Background

The growing discipline of structural systems pharmacology is applied prospectively in this study to predict pharmacological outcomes of antibacterial compounds in Escherichia coli K12. This work builds upon previously established methods for structural prediction of ligand binding pockets on protein molecules and utilizes and expands upon the previously developed genome scale model of metabolism integrated with protein structures (GEM-PRO) for E. coli, structurally accounting for protein complexes. Carefully selected case studies are demonstrated to display the potential for this structural systems pharmacology framework in discovery and development of antibacterial compounds.

Results

The prediction framework for antibacterial activity of compounds was validated for a control set of well-studied compounds, recapitulating experimentally-determined protein binding interactions and deleterious growth phenotypes resulting from these interactions. The antibacterial activity of fosfomycin, sulfathiazole, and trimethoprim were accurately predicted, and as a negative control glucose was found to have no predicted antibacterial activity. Previously uncharacterized mechanisms of action were predicted for compounds with known antibacterial properties, including (1-hydroxyheptane-1,1-diyl)bis(phosphonic acid) and cholesteryl oleate. Five candidate inhibitors were predicted for a desirable target protein without any known inhibitors, tryptophan synthase β subunit (TrpB). In addition to the predictions presented, this effort also included significant expansion of the previously developed GEM-PRO to account for physiological assemblies of protein complex structures with activities included in the E. coli K12 metabolic network.

Conclusions

The structural systems pharmacology framework presented in this study was shown to be effective in the prediction of molecular mechanisms of antibacterial compounds. The study provides a promising proof of principle for such an approach to antibacterial development and raises specific molecular and systemic hypotheses about antibacterials that are amenable to experimental testing. This framework, and perhaps also the specific predictions of antibacterials, is extensible to developing antibacterial treatments for pathogenic E. coli and other bacterial pathogens.

【 授权许可】

   
2013 Chang et al.; licensee BioMed Central Ltd.

【 图 表 】

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