dc.contributor.author | Barbosa, C | |
dc.contributor.author | Beardmore, R | |
dc.contributor.author | Schulenburg, H | |
dc.contributor.author | Jansen, G | |
dc.date.accessioned | 2018-06-08T13:54:35Z | |
dc.date.issued | 2018-04-30 | |
dc.description.abstract | The spread of antibiotic resistance is always a consequence of evolutionary processes. The consideration of evolution is thus key to the development of sustainable therapy. Two main factors were recently proposed to enhance long-term effectiveness of drug combinations: evolved collateral sensitivities between the drugs in a pair and antagonistic drug interactions. We systematically assessed these factors by performing over 1,600 evolution experiments with the opportunistic nosocomial pathogen Pseudomonas aeruginosa in single- and multidrug environments. Based on the growth dynamics during these experiments, we reconstructed antibiotic combination efficacy (ACE) networks as a new tool for characterizing the ability of the tested drug combinations to constrain bacterial survival as well as drug resistance evolution across time. Subsequent statistical analysis of the influence of the factors on ACE network characteristics revealed that (i) synergistic drug interactions increased the likelihood of bacterial population extinction-irrespective of whether combinations were compared at the same level of inhibition or not-while (ii) the potential for evolved collateral sensitivities between 2 drugs accounted for a reduction in bacterial adaptation rates. In sum, our systematic experimental analysis allowed us to pinpoint 2 complementary determinants of combination efficacy and to identify specific drug pairs with high ACE scores. Our findings can guide attempts to further improve the sustainability of antibiotic therapy by simultaneously reducing pathogen load and resistance evolution. | en_GB |
dc.description.sponsorship | Deutsche Forschungsge meinschaft (grant number SCHU1415/12-1). Individual research grant to HS and GJ. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. International Max-Planck Research School for Evolutionary Biology (grant number). Stipend to CB. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Deutsche Forschung sgemeinschaft (grant number EXC 306). Excellence Cluster Inflammation at Interfaces; infrastructural funding to HS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Max-Planck Society (grant
number). Max-Planck Fellowship to HS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. | en_GB |
dc.identifier.citation | Published online 30 April 2018 | en_GB |
dc.identifier.doi | 10.1371/journal.pbio.2004356 | |
dc.identifier.uri | http://hdl.handle.net/10871/33126 | |
dc.language.iso | en | en_GB |
dc.publisher | Public Library of Science | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/29708964 | en_GB |
dc.rights | © The Author(s). Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. | en_GB |
dc.subject | Antibiotic combination efficacy | en_GB |
dc.subject | Pseudomonas aeruginosa | en_GB |
dc.subject | antibiotic resistance | en_GB |
dc.title | Antibiotic combination efficacy (ACE) networks for a Pseudomonas aeruginosa model. | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2018-06-08T13:54:35Z | |
exeter.place-of-publication | United States | en_GB |
dc.description | This is the author accepted manuscript. The final version is available from Public Library of Science via the DOI in this record. | en_GB |
dc.identifier.journal | PLoS Biology | en_GB |