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To combat AMR pathogens, natural predators like bacteriophages and predatory bacteria have gained interest recently. Predatory bacterium Bdellovibrio bacteriovorus is ubiquitous and has a broad prey range. It is particularly potent at killing many AMR Gram-negative bacterial pathogens featured on the WHO priority list. However, it is currently unclear whether prey bacteria can evolve genetically determined resistance against predation by B. bacteriovorus. Here, we show that the model bacterium Escherichia coli K-12 consistently evolves resistance against B. bacteriovorus during experimental evolution. Selection for resistance scaled positively with predation pressure and was widespread after two cycles of predator exposure. Similar to antibiotics, predation resistance was costly, manifesting in a trade-off between predation resistance and fitness in the absence of predators. Genetic analysis combined with proteomics identified mutations that lead to the down-regulation of the outer membrane porin OmpF as a common resistance mechanism. In addition, a rarer mutation in cell envelope lipopolysaccharide-modifying enzyme WaaF also conferred predation resistance, likely by a pleiotropic effect, which included OmpF down regulation. While our study uncovers evolutionary and mechanistic aspects of prey escape from predation, it also highlights that the high cost of resistance reflects a handicap for the pathogen and can thus be exploited to increase treatment sustainability. Altogether, our work generates essential knowledge in ecologically important predator\u2013prey interactions and can advance predatory bacteria as \u201cliving antibiotics\u201d to combat AMR.<\/jats:p>","DOI":"10.1093\/ismejo\/wrag235","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T14:20:40Z","timestamp":1789568440000},"source":"Crossref","is-referenced-by-count":0,"title":["Outer membrane changes enable evolutionary escape from bacterial predation"],"prefix":"10.1093","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3120-6410","authenticated-orcid":false,"given":"Subham","family":"Mridha","sequence":"first","affiliation":[{"name":"Department of Plant and Microbial Biology, University of Zurich , Zurich CH-8008 ,","place":["Switzerland"]},{"name":"Department of Quantitative Biomedicine, University of Zurich , Zurich CH-8057 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3043-0254","authenticated-orcid":false,"given":"Ove Christopher","family":"Mattmann","sequence":"additional","affiliation":[{"name":"Department of Plant and Microbial Biology, University of Zurich , Zurich CH-8008 ,","place":["Switzerland"]},{"name":"Department of Quantitative Biomedicine, University of Zurich , Zurich CH-8057 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3231-963X","authenticated-orcid":false,"given":"Sarah-Luise","family":"Loose","sequence":"additional","affiliation":[{"name":"Department of Plant and Microbial Biology, University of Zurich , Zurich CH-8008 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4766-5099","authenticated-orcid":false,"given":"Saskia","family":"Isele","sequence":"additional","affiliation":[{"name":"Department of Plant and Microbial Biology, University of Zurich , Zurich CH-8008 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5756-9773","authenticated-orcid":false,"given":"Bernd","family":"Roschitzki","sequence":"additional","affiliation":[{"name":"Functional Genomics Center Zurich, University of Zurich\/ETH \u00a0 Zurich, Zurich CH-8057 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4084-6679","authenticated-orcid":false,"given":"Rolf","family":"K\u00fcmmerli","sequence":"additional","affiliation":[{"name":"Department of Quantitative Biomedicine, University of Zurich , Zurich CH-8057 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4876-9308","authenticated-orcid":false,"given":"Simona G","family":"Huwiler","sequence":"additional","affiliation":[{"name":"Department of Plant and Microbial Biology, University of Zurich , Zurich CH-8008 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"2026102615163077000_ref1","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/S0140-6736(21)02724-0","article-title":"Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis","volume":"399","author":"Murray","year":"2022","journal-title":"Lancet"},{"key":"2026102615163077000_ref2","doi-asserted-by":"publisher","first-page":"1434","DOI":"10.1038\/s41564-024-01705-x","article-title":"Personalized bacteriophage therapy outcomes for 100 consecutive cases: a multicentre, multinational, retrospective observational study","volume":"9","author":"Pirnay","year":"2024","journal-title":"Nat Microbiol"},{"key":"2026102615163077000_ref3","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1038\/nrmicro959","article-title":"Bdellovibrio as therapeutic agents: a predatory renaissance?","volume":"2","author":"Sockett","year":"2004","journal-title":"Nat Rev Microbiol"},{"key":"2026102615163077000_ref4","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1007\/s00284-022-03029-7","article-title":"Emerging non-traditional approaches to combat antibiotic resistance","volume":"79","author":"Konwar","year":"2022","journal-title":"Curr Microbiol"},{"key":"2026102615163077000_ref5","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1146\/annurev-virology-091919-075914","article-title":"Understanding the impacts of bacteriophage viruses: from laboratory evolution to natural ecosystems","volume":"9","author":"Koskella","year":"2022","journal-title":"Annu Rev Virol"},{"key":"2026102615163077000_ref6","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.001025","article-title":"Predatory bacteria as living antibiotics - 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