{"author":[{"id":"424D78A0-F248-11E8-B48F-1D18A9856A87","full_name":"Chevereau, Guillaume","first_name":"Guillaume","last_name":"Chevereau"},{"orcid":"0000-0003-4398-476X","last_name":"Bollenbach","first_name":"Mark Tobias","full_name":"Bollenbach, Mark Tobias","id":"3E6DB97A-F248-11E8-B48F-1D18A9856A87"}],"publication":"Molecular Systems Biology","has_accepted_license":"1","doi":"10.15252/msb.20156098","_id":"1823","article_number":"807","pubrep_id":"395","language":[{"iso":"eng"}],"citation":{"short":"G. Chevereau, M.T. Bollenbach, Molecular Systems Biology 11 (2015).","apa":"Chevereau, G., &#38; Bollenbach, M. T. (2015). Systematic discovery of drug interaction mechanisms. <i>Molecular Systems Biology</i>. Nature Publishing Group. <a href=\"https://doi.org/10.15252/msb.20156098\">https://doi.org/10.15252/msb.20156098</a>","chicago":"Chevereau, Guillaume, and Mark Tobias Bollenbach. “Systematic Discovery of Drug Interaction Mechanisms.” <i>Molecular Systems Biology</i>. Nature Publishing Group, 2015. <a href=\"https://doi.org/10.15252/msb.20156098\">https://doi.org/10.15252/msb.20156098</a>.","ista":"Chevereau G, Bollenbach MT. 2015. Systematic discovery of drug interaction mechanisms. Molecular Systems Biology. 11(4), 807.","ama":"Chevereau G, Bollenbach MT. Systematic discovery of drug interaction mechanisms. <i>Molecular Systems Biology</i>. 2015;11(4). doi:<a href=\"https://doi.org/10.15252/msb.20156098\">10.15252/msb.20156098</a>","ieee":"G. Chevereau and M. T. Bollenbach, “Systematic discovery of drug interaction mechanisms,” <i>Molecular Systems Biology</i>, vol. 11, no. 4. Nature Publishing Group, 2015.","mla":"Chevereau, Guillaume, and Mark Tobias Bollenbach. “Systematic Discovery of Drug Interaction Mechanisms.” <i>Molecular Systems Biology</i>, vol. 11, no. 4, 807, Nature Publishing Group, 2015, doi:<a href=\"https://doi.org/10.15252/msb.20156098\">10.15252/msb.20156098</a>."},"ec_funded":1,"year":"2015","intvolume":"        11","publist_id":"5283","volume":11,"project":[{"grant_number":"P27201-B22","name":"Revealing the mechanisms underlying drug interactions","_id":"25E9AF9E-B435-11E9-9278-68D0E5697425","call_identifier":"FWF"},{"grant_number":"RGP0042/2013","_id":"25EB3A80-B435-11E9-9278-68D0E5697425","name":"Revealing the fundamental limits of cell growth"},{"call_identifier":"FP7","grant_number":"303507","name":"Optimality principles in responses to antibiotics","_id":"25E83C2C-B435-11E9-9278-68D0E5697425"}],"ddc":["570"],"file_date_updated":"2020-07-14T12:45:17Z","month":"04","date_updated":"2021-01-12T06:53:26Z","tmp":{"image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"type":"journal_article","file":[{"date_updated":"2020-07-14T12:45:17Z","file_size":1273573,"date_created":"2018-12-12T10:14:34Z","file_id":"5087","relation":"main_file","checksum":"4289b518fbe2166682fb1a1ef9b405f3","file_name":"IST-2015-395-v1+1_807.full.pdf","access_level":"open_access","creator":"system","content_type":"application/pdf"}],"day":"01","department":[{"_id":"ToBo"}],"abstract":[{"lang":"eng","text":"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."}],"publication_status":"published","date_published":"2015-04-01T00:00:00Z","issue":"4","publisher":"Nature Publishing Group","scopus_import":1,"oa_version":"Published Version","oa":1,"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","date_created":"2018-12-11T11:54:12Z","quality_controlled":"1","title":"Systematic discovery of drug interaction mechanisms","status":"public"}