Systematic discovery of drug interaction mechanisms

article Systematic discovery of drug interaction mechanisms published yes Guillaume Chevereau author 424D78A0-F248-11E8-B48F-1D18A9856A87 Mark Tobias Bollenbach author 3E6DB97A-F248-11E8-B48F-1D18A9856A870000-0003-4398-476X ToBo department Revealing the mechanisms underlying drug interactions project Revealing the fundamental limits of cell growth project Optimality principles in responses to antibiotics project Abstract Drug combinations are increasingly important in disease treatments, for combating drug resistance, and for elucidating fundamental relationships in cell physiology. When drugs are combined, their individual effects on cells may be amplified or weakened. Such drug interactions are crucial for treatment efficacy, but their underlying mechanisms remain largely unknown. To uncover the causes of drug interactions, we developed a systematic approach based on precise quantification of the individual and joint effects of antibiotics on growth of genome-wide Escherichia coli gene deletion strains. We found that drug interactions between antibiotics representing the main modes of action are highly robust to genetic perturbation. This robustness is encapsulated in a general principle of bacterial growth, which enables the quantitative prediction of mutant growth rates under drug combinations. Rare violations of this principle exposed recurring cellular functions controlling drug interactions. In particular, we found that polysaccharide and ATP synthesis control multiple drug interactions with previously unexplained mechanisms, and small molecule adjuvants targeting these functions synthetically reshape drug interactions in predictable ways. These results provide a new conceptual framework for the design of multidrug combinations and suggest that there are universal mechanisms at the heart of most drug interactions. Synopsis A general principle of bacterial growth enables the prediction of mutant growth rates under drug combinations. Rare violations of this principle expose cellular functions that control drug interactions and can be targeted by small molecules to alter drug interactions in predictable ways. Drug interactions between antibiotics are highly robust to genetic perturbations. A general principle of bacterial growth enables the prediction of mutant growth rates under drug combinations. Rare violations of this principle expose cellular functions that control drug interactions. Diverse drug interactions are controlled by recurring cellular functions, including LPS synthesis and ATP synthesis. A general principle of bacterial growth enables the prediction of mutant growth rates under drug combinations. Rare violations of this principle expose cellular functions that control drug interactions and can be targeted by small molecules to alter drug interactions in predictable ways. https://research-explorer.ista.ac.at/download/1823/5087/IST-2015-395-v1+1_807.full.pdf application/pdfno https://creativecommons.org/licenses/by/4.0/ Nature Publishing Group2015 eng Molecular Systems Biology 00035402230000510.15252/msb.20156098 114 G. Chevereau, M.T. Bollenbach, Molecular Systems Biology 11 (2015). Chevereau, Guillaume, and Mark Tobias Bollenbach. “Systematic Discovery of Drug Interaction Mechanisms.” Molecular Systems Biology, vol. 11, no. 4, 807, Nature Publishing Group, 2015, doi:<a href="https://doi.org/10.15252/msb.20156098">10.15252/msb.20156098</a>. G. Chevereau and M. T. Bollenbach, “Systematic discovery of drug interaction mechanisms,” Molecular Systems Biology, vol. 11, no. 4. Nature Publishing Group, 2015. Chevereau G, Bollenbach MT. Systematic discovery of drug interaction mechanisms. Molecular Systems Biology. 2015;11(4). doi:<a href="https://doi.org/10.15252/msb.20156098">10.15252/msb.20156098</a> Chevereau, G., & Bollenbach, M. T. (2015). Systematic discovery of drug interaction mechanisms. Molecular Systems Biology. Nature Publishing Group. <a href="https://doi.org/10.15252/msb.20156098">https://doi.org/10.15252/msb.20156098</a> Chevereau, Guillaume, and Mark Tobias Bollenbach. “Systematic Discovery of Drug Interaction Mechanisms.” Molecular Systems Biology. Nature Publishing Group, 2015. <a href="https://doi.org/10.15252/msb.20156098">https://doi.org/10.15252/msb.20156098</a>. Chevereau G, Bollenbach MT. 2015. Systematic discovery of drug interaction mechanisms. Molecular Systems Biology. 11(4), 807. 18232018-12-11T11:54:12Z2025-09-23T13:38:00Z