{"year":"2022","article_type":"original","scopus_import":"1","ddc":["570"],"volume":18,"publication":"Molecular Systems Biology","oa_version":"Published Version","status":"public","title":"Growth‐mediated negative feedback shapes quantitative antibiotic response","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","department":[{"_id":"ToBo"}],"issue":"9","external_id":{"isi":["000856482800001"]},"_id":"12261","citation":{"apa":"Angermayr, A., Pang, T. Y., Chevereau, G., Mitosch, K., Lercher, M. J., &#38; Bollenbach, M. T. (2022). Growth‐mediated negative feedback shapes quantitative antibiotic response. <i>Molecular Systems Biology</i>. Embo Press. <a href=\"https://doi.org/10.15252/msb.202110490\">https://doi.org/10.15252/msb.202110490</a>","mla":"Angermayr, Andreas, et al. “Growth‐mediated Negative Feedback Shapes Quantitative Antibiotic Response.” <i>Molecular Systems Biology</i>, vol. 18, no. 9, e10490, Embo Press, 2022, doi:<a href=\"https://doi.org/10.15252/msb.202110490\">10.15252/msb.202110490</a>.","ista":"Angermayr A, Pang TY, Chevereau G, Mitosch K, Lercher MJ, Bollenbach MT. 2022. Growth‐mediated negative feedback shapes quantitative antibiotic response. Molecular Systems Biology. 18(9), e10490.","ieee":"A. Angermayr, T. Y. Pang, G. Chevereau, K. Mitosch, M. J. Lercher, and M. T. Bollenbach, “Growth‐mediated negative feedback shapes quantitative antibiotic response,” <i>Molecular Systems Biology</i>, vol. 18, no. 9. Embo Press, 2022.","ama":"Angermayr A, Pang TY, Chevereau G, Mitosch K, Lercher MJ, Bollenbach MT. Growth‐mediated negative feedback shapes quantitative antibiotic response. <i>Molecular Systems Biology</i>. 2022;18(9). doi:<a href=\"https://doi.org/10.15252/msb.202110490\">10.15252/msb.202110490</a>","chicago":"Angermayr, Andreas, Tin Yau Pang, Guillaume Chevereau, Karin Mitosch, Martin J Lercher, and Mark Tobias Bollenbach. “Growth‐mediated Negative Feedback Shapes Quantitative Antibiotic Response.” <i>Molecular Systems Biology</i>. Embo Press, 2022. <a href=\"https://doi.org/10.15252/msb.202110490\">https://doi.org/10.15252/msb.202110490</a>.","short":"A. Angermayr, T.Y. Pang, G. Chevereau, K. Mitosch, M.J. Lercher, M.T. Bollenbach, Molecular Systems Biology 18 (2022)."},"month":"09","day":"01","article_processing_charge":"No","article_number":"e10490","has_accepted_license":"1","isi":1,"acknowledgement":"This work was in part supported by Human Frontier Science Program GrantRGP0042/2013, Marie Curie Career Integration Grant303507, AustrianScience Fund (FWF) Grant P27201-B22, and German Research Foundation(DFG) Collaborative Research Center (SFB)1310to TB. SAA was supportedby the European Union’s Horizon2020Research and Innovation Programunder the Marie Skłodowska-Curie Grant agreement No707352. We wouldlike to thank the Bollenbach group for regular fruitful discussions. We areparticularly thankful for the technical assistance of Booshini Fernando andfor discussions of the theoretical aspects with Gerrit Ansmann. We areindebted to Bor Kavˇciˇc for invaluable advice, help with setting up theluciferase-based growth monitoring system, and for sharing plasmids. Weacknowledge the IST Austria Miba Machine Shop for their support inbuilding a housing for the stacker of the plate reader, which enabled thehigh-throughput luciferase-based experiments. We are grateful to RosalindAllen, Bor Kavˇciˇc and Dor Russ for feedback on the manuscript. Open Accessfunding enabled and organized by Projekt DEAL.","abstract":[{"text":"Dose–response relationships are a general concept for quantitatively describing biological systems across multiple scales, from the molecular to the whole-cell level. A clinically relevant example is the bacterial growth response to antibiotics, which is routinely characterized by dose–response curves. The shape of the dose–response curve varies drastically between antibiotics and plays a key role in treatment, drug interactions, and resistance evolution. However, the mechanisms shaping the dose–response curve remain largely unclear. Here, we show in Escherichia coli that the distinctively shallow dose–response curve of the antibiotic trimethoprim is caused by a negative growth-mediated feedback loop: Trimethoprim slows growth, which in turn weakens the effect of this antibiotic. At the molecular level, this feedback is caused by the upregulation of the drug target dihydrofolate reductase (FolA/DHFR). We show that this upregulation is not a specific response to trimethoprim but follows a universal trend line that depends primarily on the growth rate, irrespective of its cause. Rewiring the feedback loop alters the dose–response curve in a predictable manner, which we corroborate using a mathematical model of cellular resource allocation and growth. Our results indicate that growth-mediated feedback loops may shape drug responses more generally and could be exploited to design evolutionary traps that enable selection against drug resistance.","lang":"eng"}],"acknowledged_ssus":[{"_id":"M-Shop"}],"license":"https://creativecommons.org/licenses/by/4.0/","language":[{"iso":"eng"}],"date_created":"2023-01-16T09:58:34Z","publisher":"Embo Press","oa":1,"file_date_updated":"2023-01-30T09:49:55Z","doi":"10.15252/msb.202110490","file":[{"creator":"dernst","date_updated":"2023-01-30T09:49:55Z","file_size":1098812,"date_created":"2023-01-30T09:49:55Z","file_id":"12446","content_type":"application/pdf","file_name":"2022_MolecularSystemsBio_Angermayr.pdf","success":1,"relation":"main_file","access_level":"open_access","checksum":"8b1d8f5ea20c8408acf466435fb6ae01"}],"author":[{"first_name":"Andreas","last_name":"Angermayr","id":"4677C796-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-8619-2223","full_name":"Angermayr, Andreas"},{"first_name":"Tin Yau","last_name":"Pang","full_name":"Pang, Tin Yau"},{"full_name":"Chevereau, Guillaume","first_name":"Guillaume","last_name":"Chevereau"},{"full_name":"Mitosch, Karin","last_name":"Mitosch","id":"39B66846-F248-11E8-B48F-1D18A9856A87","first_name":"Karin"},{"full_name":"Lercher, Martin J","first_name":"Martin J","last_name":"Lercher"},{"last_name":"Bollenbach","id":"3E6DB97A-F248-11E8-B48F-1D18A9856A87","first_name":"Mark Tobias","full_name":"Bollenbach, Mark Tobias","orcid":"0000-0003-4398-476X"}],"keyword":["Applied Mathematics","Computational Theory and Mathematics","General Agricultural and Biological Sciences","General Immunology and Microbiology","General Biochemistry","Genetics and Molecular Biology","Information Systems"],"type":"journal_article","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"intvolume":"        18","publication_identifier":{"eissn":["1744-4292"]},"date_updated":"2023-08-04T09:51:49Z","date_published":"2022-09-01T00:00:00Z","publication_status":"published","quality_controlled":"1"}