{"abstract":[{"text":"Antibiotics that interfere with translation, when combined, interact in diverse and difficult-to-predict ways. Here, we explain these interactions by “translation bottlenecks”: points in the translation cycle where antibiotics block ribosomal progression. To elucidate the underlying mechanisms of drug interactions between translation inhibitors, we generate translation bottlenecks genetically using inducible control of translation factors that regulate well-defined translation cycle steps. These perturbations accurately mimic antibiotic action and drug interactions, supporting that the interplay of different translation bottlenecks causes these interactions. We further show that growth laws, combined with drug uptake and binding kinetics, enable the direct prediction of a large fraction of observed interactions, yet fail to predict suppression. However, varying two translation bottlenecks simultaneously supports that dense traffic of ribosomes and competition for translation factors account for the previously unexplained suppression. These results highlight the importance of “continuous epistasis” in bacterial physiology.","lang":"eng"}],"status":"public","tmp":{"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","image":"/images/cc_by.png"},"date_updated":"2024-06-29T22:30:10Z","intvolume":"        11","quality_controlled":"1","day":"11","acknowledgement":"We thank M. Hennessey-Wesen, I. Tomanek, K. Jain, A. Staron, K. Tomasek, M. Scott,\r\nK.C. Huang, and Z. Gitai for reading the manuscript and constructive comments. B.K. is\r\nindebted to C. Guet for additional guidance and generous support, which rendered this\r\nwork possible. B.K. thanks all members of Guet group for many helpful discussions and\r\nsharing of resources. B.K. additionally acknowledges the tremendous support from A.\r\nAngermayr and K. Mitosch with experimental work. We further thank E. Brown for\r\nhelpful comments regarding lamotrigine, and A. Buskirk for valuable suggestions\r\nregarding the ribosome footprint size. This work was supported in part by Austrian\r\nScience Fund (FWF) standalone grants P 27201-B22 (to T.B.) and P 28844 (to G.T.),\r\nHFSP program Grant RGP0042/2013 (to T.B.), German Research Foundation (DFG)\r\nstandalone grant BO 3502/2-1 (to T.B.), and German Research Foundation (DFG)\r\nCollaborative Research Centre (SFB) 1310 (to T.B.). Open access funding provided by\r\nProjekt DEAL.","related_material":{"record":[{"id":"8657","status":"public","relation":"dissertation_contains"}]},"project":[{"name":"Revealing the mechanisms underlying drug interactions","_id":"25E9AF9E-B435-11E9-9278-68D0E5697425","grant_number":"P27201-B22","call_identifier":"FWF"},{"_id":"254E9036-B435-11E9-9278-68D0E5697425","name":"Biophysics of information processing in gene regulation","grant_number":"P28844-B27","call_identifier":"FWF"}],"isi":1,"volume":11,"external_id":{"isi":["000562769300008"]},"has_accepted_license":"1","article_type":"original","date_created":"2020-08-12T09:13:50Z","article_number":"4013","publication":"Nature Communications","date_published":"2020-08-11T00:00:00Z","article_processing_charge":"No","year":"2020","file":[{"date_updated":"2020-08-17T07:36:57Z","content_type":"application/pdf","date_created":"2020-08-17T07:36:57Z","file_name":"2020_NatureComm_Kavcic.pdf","file_size":1965672,"relation":"main_file","success":1,"access_level":"open_access","file_id":"8275","checksum":"986bebb308850a55850028d3d2b5b664","creator":"dernst"}],"ddc":["570"],"author":[{"full_name":"Kavcic, Bor","first_name":"Bor","orcid":"0000-0001-6041-254X","id":"350F91D2-F248-11E8-B48F-1D18A9856A87","last_name":"Kavcic"},{"first_name":"Gašper","orcid":"0000-0002-6699-1455","full_name":"Tkačik, Gašper","id":"3D494DCA-F248-11E8-B48F-1D18A9856A87","last_name":"Tkačik"},{"last_name":"Bollenbach","id":"3E6DB97A-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-4398-476X","first_name":"Tobias","full_name":"Bollenbach, Tobias"}],"language":[{"iso":"eng"}],"file_date_updated":"2020-08-17T07:36:57Z","department":[{"_id":"GaTk"}],"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","oa":1,"publisher":"Springer Nature","publication_status":"published","month":"08","title":"Mechanisms of drug interactions between translation-inhibiting antibiotics","doi":"10.1038/s41467-020-17734-z","publication_identifier":{"issn":["2041-1723"]},"_id":"8250","type":"journal_article","citation":{"short":"B. Kavcic, G. Tkačik, M.T. Bollenbach, Nature Communications 11 (2020).","apa":"Kavcic, B., Tkačik, G., &#38; Bollenbach, M. T. (2020). Mechanisms of drug interactions between translation-inhibiting antibiotics. <i>Nature Communications</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41467-020-17734-z\">https://doi.org/10.1038/s41467-020-17734-z</a>","ista":"Kavcic B, Tkačik G, Bollenbach MT. 2020. Mechanisms of drug interactions between translation-inhibiting antibiotics. Nature Communications. 11, 4013.","ama":"Kavcic B, Tkačik G, Bollenbach MT. Mechanisms of drug interactions between translation-inhibiting antibiotics. <i>Nature Communications</i>. 2020;11. doi:<a href=\"https://doi.org/10.1038/s41467-020-17734-z\">10.1038/s41467-020-17734-z</a>","mla":"Kavcic, Bor, et al. “Mechanisms of Drug Interactions between Translation-Inhibiting Antibiotics.” <i>Nature Communications</i>, vol. 11, 4013, Springer Nature, 2020, doi:<a href=\"https://doi.org/10.1038/s41467-020-17734-z\">10.1038/s41467-020-17734-z</a>.","chicago":"Kavcic, Bor, Gašper Tkačik, and Mark Tobias Bollenbach. “Mechanisms of Drug Interactions between Translation-Inhibiting Antibiotics.” <i>Nature Communications</i>. Springer Nature, 2020. <a href=\"https://doi.org/10.1038/s41467-020-17734-z\">https://doi.org/10.1038/s41467-020-17734-z</a>.","ieee":"B. Kavcic, G. Tkačik, and M. T. Bollenbach, “Mechanisms of drug interactions between translation-inhibiting antibiotics,” <i>Nature Communications</i>, vol. 11. Springer Nature, 2020."},"oa_version":"Published Version"}