[{"doi":"10.3389/fmicb.2021.760017","date_published":"2021-10-20T00:00:00Z","date_created":"2021-11-11T10:39:37Z","has_accepted_license":"1","isi":1,"year":"2021","day":"20","publication":"Frontiers in Microbiology","quality_controlled":"1","publisher":"Frontiers","oa":1,"acknowledgement":"High-throughput sequencing data were generated by the Vienna BioCenter Core Facilities. The authors would like to thank Karin Mitosch, Bor Kavcic, and Nadine Kraupner for their constructive feedback. The authors would also like to thank Gertraud Stift, Julia Flor, Renate Srsek, Agnieszka Wiktor, and Booshini Fernando for technical support.","author":[{"orcid":"0000-0002-6148-2416","full_name":"Qi, Qin","last_name":"Qi","id":"3B22D412-F248-11E8-B48F-1D18A9856A87","first_name":"Qin"},{"first_name":"S. Andreas","last_name":"Angermayr","full_name":"Angermayr, S. Andreas"},{"id":"3E6DB97A-F248-11E8-B48F-1D18A9856A87","first_name":"Mark Tobias","full_name":"Bollenbach, Mark Tobias","orcid":"0000-0003-4398-476X","last_name":"Bollenbach"}],"external_id":{"isi":["000715997300001"],"pmid":["34745067"]},"article_processing_charge":"No","title":"Uncovering Key Metabolic Determinants of the Drug Interactions Between Trimethoprim and Erythromycin in Escherichia coli","citation":{"chicago":"Qi, Qin, S. Andreas Angermayr, and Mark Tobias Bollenbach. “Uncovering Key Metabolic Determinants of the Drug Interactions Between Trimethoprim and Erythromycin in Escherichia Coli.” Frontiers in Microbiology. Frontiers, 2021. https://doi.org/10.3389/fmicb.2021.760017.","ista":"Qi Q, Angermayr SA, Bollenbach MT. 2021. Uncovering Key Metabolic Determinants of the Drug Interactions Between Trimethoprim and Erythromycin in Escherichia coli. Frontiers in Microbiology. 12, 760017.","mla":"Qi, Qin, et al. “Uncovering Key Metabolic Determinants of the Drug Interactions Between Trimethoprim and Erythromycin in Escherichia Coli.” Frontiers in Microbiology, vol. 12, 760017, Frontiers, 2021, doi:10.3389/fmicb.2021.760017.","apa":"Qi, Q., Angermayr, S. A., & Bollenbach, M. T. (2021). Uncovering Key Metabolic Determinants of the Drug Interactions Between Trimethoprim and Erythromycin in Escherichia coli. Frontiers in Microbiology. Frontiers. https://doi.org/10.3389/fmicb.2021.760017","ama":"Qi Q, Angermayr SA, Bollenbach MT. Uncovering Key Metabolic Determinants of the Drug Interactions Between Trimethoprim and Erythromycin in Escherichia coli. Frontiers in Microbiology. 2021;12. doi:10.3389/fmicb.2021.760017","short":"Q. Qi, S.A. Angermayr, M.T. Bollenbach, Frontiers in Microbiology 12 (2021).","ieee":"Q. Qi, S. A. Angermayr, and M. T. Bollenbach, “Uncovering Key Metabolic Determinants of the Drug Interactions Between Trimethoprim and Erythromycin in Escherichia coli,” Frontiers in Microbiology, vol. 12. Frontiers, 2021."},"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","project":[{"name":"Revealing the mechanisms underlying drug interactions","grant_number":"P27201-B22","call_identifier":"FWF","_id":"25E9AF9E-B435-11E9-9278-68D0E5697425"},{"grant_number":"303507","name":"Optimality principles in responses to antibiotics","_id":"25E83C2C-B435-11E9-9278-68D0E5697425","call_identifier":"FP7"}],"article_number":"760017","volume":12,"ec_funded":1,"license":"https://creativecommons.org/licenses/by/4.0/","publication_identifier":{"eissn":["1664-302X"]},"publication_status":"published","file":[{"file_id":"10272","checksum":"d41321748e9588dd3cf03e9a7222127f","success":1,"content_type":"application/pdf","access_level":"open_access","relation":"main_file","date_created":"2021-11-11T10:54:40Z","file_name":"2021_FrontiersMicrob_Qi.pdf","date_updated":"2021-11-11T10:54:40Z","file_size":2397203,"creator":"cchlebak"}],"language":[{"iso":"eng"}],"scopus_import":"1","month":"10","intvolume":" 12","abstract":[{"text":"Understanding interactions between antibiotics used in combination is an important theme in microbiology. Using the interactions between the antifolate drug trimethoprim and the ribosome-targeting antibiotic erythromycin in Escherichia coli as a model, we applied a transcriptomic approach for dissecting interactions between two antibiotics with different modes of action. When trimethoprim and erythromycin were combined, the transcriptional response of genes from the sulfate reduction pathway deviated from the dominant effect of trimethoprim on the transcriptome. We successfully altered the drug interaction from additivity to suppression by increasing the sulfate level in the growth environment and identified sulfate reduction as an important metabolic determinant that shapes the interaction between the two drugs. Our work highlights the potential of using prioritization of gene expression patterns as a tool for identifying key metabolic determinants that shape drug-drug interactions. We further demonstrated that the sigma factor-binding protein gene crl shapes the interactions between the two antibiotics, which provides a rare example of how naturally occurring variations between strains of the same bacterial species can sometimes generate very different drug interactions.","lang":"eng"}],"oa_version":"Published Version","pmid":1,"file_date_updated":"2021-11-11T10:54:40Z","date_updated":"2023-08-14T11:43:23Z","ddc":["610"],"article_type":"original","type":"journal_article","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"status":"public","keyword":["microbiology"],"_id":"10271"},{"status":"public","pubrep_id":"488","type":"journal_article","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"_id":"1552","department":[{"_id":"ToBo"}],"file_date_updated":"2020-07-14T12:45:02Z","ddc":["570"],"date_updated":"2021-01-12T06:51:33Z","month":"01","intvolume":" 283","scopus_import":1,"oa_version":"Published Version","abstract":[{"lang":"eng","text":"Antibiotic resistance carries a fitness cost that must be overcome in order for resistance to persist over the long term. Compensatory mutations that recover the functional defects associated with resistance mutations have been argued to play a key role in overcoming the cost of resistance, but compensatory mutations are expected to be rare relative to generally beneficial mutations that increase fitness, irrespective of antibiotic resistance. Given this asymmetry, population genetics theory predicts that populations should adapt by compensatory mutations when the cost of resistance is large, whereas generally beneficial mutations should drive adaptation when the cost of resistance is small. We tested this prediction by determining the genomic mechanisms underpinning adaptation to antibiotic-free conditions in populations of the pathogenic bacterium Pseudomonas aeruginosa that carry costly antibiotic resistance mutations. Whole-genome sequencing revealed that populations founded by high-cost rifampicin-resistant mutants adapted via compensatory mutations in three genes of the RNA polymerase core enzyme, whereas populations founded by low-cost mutants adapted by generally beneficial mutations, predominantly in the quorum-sensing transcriptional regulator gene lasR. Even though the importance of compensatory evolution in maintaining resistance has been widely recognized, our study shows that the roles of general adaptation in maintaining resistance should not be underestimated and highlights the need to understand how selection at other sites in the genome influences the dynamics of resistance alleles in clinical settings."}],"volume":283,"issue":"1822","file":[{"date_created":"2018-12-12T10:11:43Z","file_name":"IST-2016-488-v1+1_20152452.full.pdf","creator":"system","date_updated":"2020-07-14T12:45:02Z","file_size":626804,"checksum":"78ffe70c1c88af3856d31ca6b7195a27","file_id":"4899","access_level":"open_access","relation":"main_file","content_type":"application/pdf"}],"language":[{"iso":"eng"}],"publication_status":"published","article_number":"20152452","title":"The genomic basis of adaptation to the fitness cost of rifampicin resistance in Pseudomonas aeruginosa","author":[{"last_name":"Qi","orcid":"0000-0002-6148-2416","full_name":"Qi, Qin","first_name":"Qin","id":"3B22D412-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Macarena","last_name":"Toll Riera","full_name":"Toll Riera, Macarena"},{"first_name":"Karl","full_name":"Heilbron, Karl","last_name":"Heilbron"},{"full_name":"Preston, Gail","last_name":"Preston","first_name":"Gail"},{"first_name":"R Craig","last_name":"Maclean","full_name":"Maclean, R Craig"}],"publist_id":"5619","user_id":"3E5EF7F0-F248-11E8-B48F-1D18A9856A87","citation":{"ieee":"Q. Qi, M. Toll Riera, K. Heilbron, G. Preston, and R. C. Maclean, “The genomic basis of adaptation to the fitness cost of rifampicin resistance in Pseudomonas aeruginosa,” Proceedings of the Royal Society of London Series B Biological Sciences, vol. 283, no. 1822. Royal Society, The, 2016.","short":"Q. Qi, M. Toll Riera, K. Heilbron, G. Preston, R.C. Maclean, Proceedings of the Royal Society of London Series B Biological Sciences 283 (2016).","apa":"Qi, Q., Toll Riera, M., Heilbron, K., Preston, G., & Maclean, R. C. (2016). The genomic basis of adaptation to the fitness cost of rifampicin resistance in Pseudomonas aeruginosa. Proceedings of the Royal Society of London Series B Biological Sciences. Royal Society, The. https://doi.org/10.1098/rspb.2015.2452","ama":"Qi Q, Toll Riera M, Heilbron K, Preston G, Maclean RC. The genomic basis of adaptation to the fitness cost of rifampicin resistance in Pseudomonas aeruginosa. Proceedings of the Royal Society of London Series B Biological Sciences. 2016;283(1822). doi:10.1098/rspb.2015.2452","mla":"Qi, Qin, et al. “The Genomic Basis of Adaptation to the Fitness Cost of Rifampicin Resistance in Pseudomonas Aeruginosa.” Proceedings of the Royal Society of London Series B Biological Sciences, vol. 283, no. 1822, 20152452, Royal Society, The, 2016, doi:10.1098/rspb.2015.2452.","ista":"Qi Q, Toll Riera M, Heilbron K, Preston G, Maclean RC. 2016. The genomic basis of adaptation to the fitness cost of rifampicin resistance in Pseudomonas aeruginosa. Proceedings of the Royal Society of London Series B Biological Sciences. 283(1822), 20152452.","chicago":"Qi, Qin, Macarena Toll Riera, Karl Heilbron, Gail Preston, and R Craig Maclean. “The Genomic Basis of Adaptation to the Fitness Cost of Rifampicin Resistance in Pseudomonas Aeruginosa.” Proceedings of the Royal Society of London Series B Biological Sciences. Royal Society, The, 2016. https://doi.org/10.1098/rspb.2015.2452."},"publisher":"Royal Society, The","quality_controlled":"1","oa":1,"acknowledgement":"We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics funded by Wellcome\r\nTrust grant reference 090532/Z/09/Z and Medical Research Council Hub grant no. G0900747 91070 for generation of the high-throughput sequencing data. We thank Wook Kim and two anonymous reviewers for their constructive feedback on previous versions of our manuscript.","doi":"10.1098/rspb.2015.2452","date_published":"2016-01-13T00:00:00Z","date_created":"2018-12-11T11:52:40Z","day":"13","publication":"Proceedings of the Royal Society of London Series B Biological Sciences","has_accepted_license":"1","year":"2016"}]