--- _id: '10812' abstract: - lang: eng text: Several promising strategies based on combining or cycling different antibiotics have been proposed to increase efficacy and counteract resistance evolution, but we still lack a deep understanding of the physiological responses and genetic mechanisms that underlie antibiotic interactions and the clinical applicability of these strategies. In antibiotic-exposed bacteria, the combined effects of physiological stress responses and emerging resistance mutations (occurring at different time scales) generate complex and often unpredictable dynamics. In this Review, we present our current understanding of bacterial cell physiology and genetics of responses to antibiotics. We emphasize recently discovered mechanisms of synergistic and antagonistic drug interactions, hysteresis in temporal interactions between antibiotics that arise from microbial physiology and interactions between antibiotics and resistance mutations that can cause collateral sensitivity or cross-resistance. We discuss possible connections between the different phenomena and indicate relevant research directions. A better and more unified understanding of drug and genetic interactions is likely to advance antibiotic therapy. acknowledgement: The authors thank B. Kavčič and H. Schulenburg for constructive feedback on the manuscript. article_processing_charge: No article_type: review author: - first_name: Roderich full_name: Römhild, Roderich id: 68E56E44-62B0-11EA-B963-444F3DDC885E last_name: Römhild orcid: 0000-0001-9480-5261 - first_name: Mark Tobias full_name: Bollenbach, Mark Tobias id: 3E6DB97A-F248-11E8-B48F-1D18A9856A87 last_name: Bollenbach orcid: 0000-0003-4398-476X - first_name: Dan I. full_name: Andersson, Dan I. last_name: Andersson citation: ama: Römhild R, Bollenbach MT, Andersson DI. The physiology and genetics of bacterial responses to antibiotic combinations. Nature Reviews Microbiology. 2022;20:478-490. doi:10.1038/s41579-022-00700-5 apa: Römhild, R., Bollenbach, M. T., & Andersson, D. I. (2022). The physiology and genetics of bacterial responses to antibiotic combinations. Nature Reviews Microbiology. Springer Nature. https://doi.org/10.1038/s41579-022-00700-5 chicago: Römhild, Roderich, Mark Tobias Bollenbach, and Dan I. Andersson. “The Physiology and Genetics of Bacterial Responses to Antibiotic Combinations.” Nature Reviews Microbiology. Springer Nature, 2022. https://doi.org/10.1038/s41579-022-00700-5. ieee: R. Römhild, M. T. Bollenbach, and D. I. Andersson, “The physiology and genetics of bacterial responses to antibiotic combinations,” Nature Reviews Microbiology, vol. 20. Springer Nature, pp. 478–490, 2022. ista: Römhild R, Bollenbach MT, Andersson DI. 2022. The physiology and genetics of bacterial responses to antibiotic combinations. Nature Reviews Microbiology. 20, 478–490. mla: Römhild, Roderich, et al. “The Physiology and Genetics of Bacterial Responses to Antibiotic Combinations.” Nature Reviews Microbiology, vol. 20, Springer Nature, 2022, pp. 478–90, doi:10.1038/s41579-022-00700-5. short: R. Römhild, M.T. Bollenbach, D.I. Andersson, Nature Reviews Microbiology 20 (2022) 478–490. date_created: 2022-03-04T04:33:49Z date_published: 2022-08-01T00:00:00Z date_updated: 2023-08-02T14:41:44Z day: '01' department: - _id: CaGu doi: 10.1038/s41579-022-00700-5 external_id: isi: - '000763891900001' pmid: - '35241807' intvolume: ' 20' isi: 1 keyword: - General Immunology and Microbiology - Microbiology - Infectious Diseases language: - iso: eng month: '08' oa_version: None page: 478-490 pmid: 1 publication: Nature Reviews Microbiology publication_identifier: eissn: - 1740-1534 issn: - 1740-1526 publication_status: published publisher: Springer Nature quality_controlled: '1' scopus_import: '1' status: public title: The physiology and genetics of bacterial responses to antibiotic combinations type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 20 year: '2022' ... --- _id: '9046' acknowledgement: Our work was supported by the Swedish Research Council (grant 2017-01527) to DIA article_number: e1009172 article_processing_charge: No article_type: original author: - first_name: Roderich full_name: Römhild, Roderich id: 68E56E44-62B0-11EA-B963-444F3DDC885E last_name: Römhild orcid: 0000-0001-9480-5261 - first_name: Dan I. full_name: Andersson, Dan I. last_name: Andersson citation: ama: Römhild R, Andersson DI. Mechanisms and therapeutic potential of collateral sensitivity to antibiotics. PLoS Pathogens. 2021;17(1). doi:10.1371/journal.ppat.1009172 apa: Römhild, R., & Andersson, D. I. (2021). Mechanisms and therapeutic potential of collateral sensitivity to antibiotics. PLoS Pathogens. Public Library of Science. https://doi.org/10.1371/journal.ppat.1009172 chicago: Römhild, Roderich, and Dan I. Andersson. “Mechanisms and Therapeutic Potential of Collateral Sensitivity to Antibiotics.” PLoS Pathogens. Public Library of Science, 2021. https://doi.org/10.1371/journal.ppat.1009172. ieee: R. Römhild and D. I. Andersson, “Mechanisms and therapeutic potential of collateral sensitivity to antibiotics,” PLoS Pathogens, vol. 17, no. 1. Public Library of Science, 2021. ista: Römhild R, Andersson DI. 2021. Mechanisms and therapeutic potential of collateral sensitivity to antibiotics. PLoS Pathogens. 17(1), e1009172. mla: Römhild, Roderich, and Dan I. Andersson. “Mechanisms and Therapeutic Potential of Collateral Sensitivity to Antibiotics.” PLoS Pathogens, vol. 17, no. 1, e1009172, Public Library of Science, 2021, doi:10.1371/journal.ppat.1009172. short: R. Römhild, D.I. Andersson, PLoS Pathogens 17 (2021). date_created: 2021-01-31T23:01:21Z date_published: 2021-01-14T00:00:00Z date_updated: 2023-08-07T13:36:55Z day: '14' ddc: - '570' department: - _id: CaGu doi: 10.1371/journal.ppat.1009172 external_id: isi: - '000610190400007' pmid: - '33444399' file: - access_level: open_access checksum: d745d7f8fcbb9b95fea16a36f94dee31 content_type: application/pdf creator: dernst date_created: 2021-02-03T12:13:03Z date_updated: 2021-02-03T12:13:03Z file_id: '9070' file_name: 2021_PlosPathogens_Roemhild.pdf file_size: 570066 relation: main_file success: 1 file_date_updated: 2021-02-03T12:13:03Z has_accepted_license: '1' intvolume: ' 17' isi: 1 issue: '1' language: - iso: eng license: https://creativecommons.org/licenses/by/4.0/ month: '01' oa: 1 oa_version: Published Version pmid: 1 publication: PLoS Pathogens publication_identifier: eissn: - '15537374' issn: - '15537366' publication_status: published publisher: Public Library of Science quality_controlled: '1' scopus_import: '1' status: public title: Mechanisms and therapeutic potential of collateral sensitivity to antibiotics tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 17 year: '2021' ... --- _id: '9746' abstract: - lang: eng text: Evolutionary adaptation is a major source of antibiotic resistance in bacterial pathogens. Evolution-informed therapy aims to constrain resistance by accounting for bacterial evolvability. Sequential treatments with antibiotics that target different bacterial processes were previously shown to limit adaptation through genetic resistance trade-offs and negative hysteresis. Treatment with homogeneous sets of antibiotics is generally viewed to be disadvantageous, as it should rapidly lead to cross-resistance. We here challenged this assumption by determining the evolutionary response of Pseudomonas aeruginosa to experimental sequential treatments involving both heterogenous and homogeneous antibiotic sets. To our surprise, we found that fast switching between only β-lactam antibiotics resulted in increased extinction of bacterial populations. We demonstrate that extinction is favored by low rates of spontaneous resistance emergence and low levels of spontaneous cross-resistance among the antibiotics in sequence. The uncovered principles may help to guide the optimized use of available antibiotics in highly potent, evolution-informed treatment designs. acknowledgement: We would like to thank Leif Tueffers and João Botelho for discussions and suggestions as well as Kira Haas and Julia Bunk for technical support. We acknowledge financial support from the German Science Foundation (grant SCHU 1415/12-2 to HS, and funding under Germany’s Excellence Strategy EXC 2167–390884018 as well as the Research Training Group 2501 TransEvo to HS and SN), the Max Planck Society (IMPRS scholarship to AB; Max-Planck fellowship to HS), and the Leibniz Science Campus Evolutionary Medicine of the Lung (EvoLUNG, to HS and SN). This work was further supported by the German Science Foundation Research Infrastructure NGS_CC (project 407495230) as part of the Next Generation Sequencing Competence Network (project 423957469). NGS analyses were carried out at the Competence Centre for Genomic Analysis Kiel (CCGA Kiel). article_number: e68876 article_processing_charge: No article_type: original author: - first_name: Aditi full_name: Batra, Aditi last_name: Batra - first_name: Roderich full_name: Römhild, Roderich id: 68E56E44-62B0-11EA-B963-444F3DDC885E last_name: Römhild orcid: 0000-0001-9480-5261 - first_name: Emilie full_name: Rousseau, Emilie last_name: Rousseau - first_name: Sören full_name: Franzenburg, Sören last_name: Franzenburg - first_name: Stefan full_name: Niemann, Stefan last_name: Niemann - first_name: Hinrich full_name: Schulenburg, Hinrich last_name: Schulenburg citation: ama: Batra A, Römhild R, Rousseau E, Franzenburg S, Niemann S, Schulenburg H. High potency of sequential therapy with only beta-lactam antibiotics. eLife. 2021;10. doi:10.7554/elife.68876 apa: Batra, A., Römhild, R., Rousseau, E., Franzenburg, S., Niemann, S., & Schulenburg, H. (2021). High potency of sequential therapy with only beta-lactam antibiotics. ELife. eLife Sciences Publications. https://doi.org/10.7554/elife.68876 chicago: Batra, Aditi, Roderich Römhild, Emilie Rousseau, Sören Franzenburg, Stefan Niemann, and Hinrich Schulenburg. “High Potency of Sequential Therapy with Only Beta-Lactam Antibiotics.” ELife. eLife Sciences Publications, 2021. https://doi.org/10.7554/elife.68876. ieee: A. Batra, R. Römhild, E. Rousseau, S. Franzenburg, S. Niemann, and H. Schulenburg, “High potency of sequential therapy with only beta-lactam antibiotics,” eLife, vol. 10. eLife Sciences Publications, 2021. ista: Batra A, Römhild R, Rousseau E, Franzenburg S, Niemann S, Schulenburg H. 2021. High potency of sequential therapy with only beta-lactam antibiotics. eLife. 10, e68876. mla: Batra, Aditi, et al. “High Potency of Sequential Therapy with Only Beta-Lactam Antibiotics.” ELife, vol. 10, e68876, eLife Sciences Publications, 2021, doi:10.7554/elife.68876. short: A. Batra, R. Römhild, E. Rousseau, S. Franzenburg, S. Niemann, H. Schulenburg, ELife 10 (2021). date_created: 2021-07-28T13:36:57Z date_published: 2021-07-28T00:00:00Z date_updated: 2023-08-11T10:26:29Z day: '28' department: - _id: CaGu doi: 10.7554/elife.68876 external_id: isi: - '000692027800001' pmid: - '34318749' intvolume: ' 10' isi: 1 language: - iso: eng main_file_link: - open_access: '1' url: https://doi.org/10.7554/eLife.68876 month: '07' oa: 1 oa_version: Published Version pmid: 1 publication: eLife publication_identifier: eissn: - 2050-084X publication_status: published publisher: eLife Sciences Publications quality_controlled: '1' scopus_import: '1' status: public title: High potency of sequential therapy with only beta-lactam antibiotics type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 10 year: '2021' ...