{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T04:26:15Z","timestamp":1774499175053,"version":"3.50.1"},"reference-count":24,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,6,2]],"date-time":"2020-06-02T00:00:00Z","timestamp":1591056000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["252411"],"award-info":[{"award-number":["252411"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["297049"],"award-info":[{"award-number":["297049"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["322204"],"award-info":[{"award-number":["322204"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004756","name":"Emil Aaltosen S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","award":["MJ01"],"award-info":[{"award-number":["MJ01"]}],"id":[{"id":"10.13039\/501100004756","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004012","name":"Jane ja Aatos Erkon S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","award":["MJ01"],"award-info":[{"award-number":["MJ01"]}],"id":[{"id":"10.13039\/501100004012","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Beta-lactams are commonly used antibiotics that prevent cell-wall biosynthesis. Beta-lactam sensitive bacteria can acquire conjugative resistance elements and hence become resistant even after being exposed to lethal (above minimum inhibitory) antibiotic concentrations. Here we show that neither the length of antibiotic exposure (1 to 16 h) nor the beta-lactam type (penam or cephem) have a major impact on the rescue of sensitive bacteria. We demonstrate that an evolutionary rescue can occur between different clinically relevant bacterial species (Klebsiella pneumoniae and Escherichia coli) by plasmids that are commonly associated with extended-spectrum beta-lactamase (ESBL) positive hospital isolates. As such, it is possible that this resistance dynamic may play a role in failing antibiotic therapies in those cases where resistant bacteria may readily migrate into the proximity of sensitive pathogens. Furthermore, we engineered a Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-plasmid to encode a guiding CRISPR-RNA against the migrating ESBL-plasmid. By introducing this plasmid into the sensitive bacterium, the frequency of the evolutionarily rescued bacteria decreased by several orders of magnitude. As such, engineering pathogens during antibiotic treatment may provide ways to prevent ESBL-plasmid dispersal and hence resistance evolution.<\/jats:p>","DOI":"10.3390\/antibiotics9060296","type":"journal-article","created":{"date-parts":[[2020,6,3]],"date-time":"2020-06-03T04:12:09Z","timestamp":1591157529000},"page":"296","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Beta-Lactam Sensitive Bacteria Can Acquire ESBL-Resistance via Conjugation after Long-Term Exposure to Lethal Antibiotic Concentration"],"prefix":"10.3390","volume":"9","author":[{"given":"Pilvi","family":"Ruotsalainen","sequence":"first","affiliation":[{"name":"Nanoscience Center, Department of Biological and Environmental Science, University of Jyv\u00e4skyl\u00e4, P.O. Box 35, FI-40014 Jyv\u00e4skyl\u00e4, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cindy","family":"Given","sequence":"additional","affiliation":[{"name":"Nanoscience Center, Department of Biological and Environmental Science, University of Jyv\u00e4skyl\u00e4, P.O. Box 35, FI-40014 Jyv\u00e4skyl\u00e4, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reetta","family":"Penttinen","sequence":"additional","affiliation":[{"name":"Nanoscience Center, Department of Biological and Environmental Science, University of Jyv\u00e4skyl\u00e4, P.O. Box 35, FI-40014 Jyv\u00e4skyl\u00e4, Finland"},{"name":"Faculty of Science and Engineering, Department of Biology, University of Turku, FI-20014 Turku, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matti","family":"Jalasvuori","sequence":"additional","affiliation":[{"name":"Nanoscience Center, Department of Biological and Environmental Science, University of Jyv\u00e4skyl\u00e4, P.O. Box 35, FI-40014 Jyv\u00e4skyl\u00e4, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/nrmicro3270","article-title":"Microbiological effects of sublethal levels of antibiotics","volume":"12","author":"Andersson","year":"2014","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e00104-18","DOI":"10.1128\/mSystems.00104-18","article-title":"Black Queen evolution and trophic interactions determine plasmid survival after the disruption of conjugation network","volume":"3","author":"Cairns","year":"2018","journal-title":"mSystems"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1038\/s41467-017-01532-1","article-title":"Persistence and reversal of plasmid-mediated antibiotic resistance","volume":"8","author":"Lopatkin","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4207","DOI":"10.1021\/jo400236f","article-title":"Overcoming resistance to \u03b2-lactam antibiotics","volume":"78","author":"Worthington","year":"2013","journal-title":"J. Org. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"263","DOI":"10.4103\/0974-777X.68531","article-title":"Extended-spectrum \u03b2-lactamases in Gram Negative Bacteria","volume":"2","author":"Rawat","year":"2010","journal-title":"J. Glob. Infect Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/msb.2013.39","article-title":"Bacterial cheating drives the population dynamics of cooperative antibiotic resistance plasmids","volume":"9","author":"Yurtsev","year":"2013","journal-title":"Mol. Syst. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.jgar.2014.02.005","article-title":"Evolutionary rescue of bacteria via horizontal gene transfer under a lethal \u03b2-lactam concentration","volume":"2","author":"Ojala","year":"2014","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.mib.2014.09.003","article-title":"Collective antibiotic resistance: Mechanisms and implications","volume":"21","author":"Vega","year":"2014","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2524","DOI":"10.1128\/AAC.02441-15","article-title":"Selective conditions for a multidrug resistance plasmid depend on the sociality of antibiotic resistance","volume":"60","author":"Bottery","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1128\/CMR.00023-13","article-title":"Trends in human fecal carriage of extended-spectrum \u03b2-lactamases in the community: Toward the globalization of CTX-M","volume":"26","author":"Woerther","year":"2013","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1038\/ja.2017.41","article-title":"Conjugative ESBL plasmids differ in their potential to rescue susceptible bacteria via horizontal gene transfer in lethal antibiotic concentrations","volume":"70","author":"Mattila","year":"2017","journal-title":"J. Antibiot."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Cross, T., Ransegnola, B., Shin, J.H., Weaver, A., Fauntleroy, K., VanNieuwenhze, M., Westblade, L.F., and D\u00f6rr, T. (2019). Spheroplast-mediated carbapenem tolerance in Gram-negative pathogens. bioRxiv, 578559.","DOI":"10.1101\/578559"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1038\/ismej.2015.154","article-title":"Live to cheat another day: Bacterial dormancy facilitates the social exploitation of \u03b2-lactamases","volume":"10","author":"Medaney","year":"2015","journal-title":"ISME J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"999","DOI":"10.2217\/fmb-2016-0038","article-title":"Scoping the effectiveness and evolutionary obstacles in utilizing plasmid-dependent phages to fight antibiotic resistance","volume":"11","author":"Ojala","year":"2016","journal-title":"Future Microbiol."},{"key":"ref_15","first-page":"3","article-title":"General principles for the formation and proliferation of a wall-free (L-form) state in bacteria","volume":"30","author":"Mercier","year":"2014","journal-title":"eLife"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4471","DOI":"10.1007\/s00018-016-2302-2","article-title":"Morphological and ultrastructural changes in bacterial cells as an indicator of antibacterial mechanism of action","volume":"73","author":"Cushnie","year":"2016","journal-title":"Cell. Mol. Life. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1073\/pnas.84.8.2297","article-title":"Pressure-sensitive ion channel in Escherichia coli","volume":"84","author":"Martinac","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7267","DOI":"10.1073\/pnas.1500107112","article-title":"Temperate and lytic bacteriophages programmed to sensitize and kill antibiotic-resistant bacteria","volume":"112","author":"Yosef","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1080\/19490976.2019.1591136","article-title":"Midbiotics: Conjugative plasmids for genetic engineering of natural gut flora","volume":"10","author":"Ruotsalainen","year":"2019","journal-title":"Gut Microbes"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1101\/gr.2289704","article-title":"Mauve: Multiple alignment of conserved genomic sequence with rearrangements","volume":"14","author":"Darling","year":"2004","journal-title":"Genome Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"W229","DOI":"10.1093\/nar\/gky352","article-title":"oriTfinder: A web-based tool for the identification of origin of transfers in DNA sequences of bacterial mobile genetic elements","volume":"46","author":"Li","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"482","DOI":"10.3389\/fmicb.2014.00482","article-title":"Ori-Finder 2, an integrated tool to predict replication origins in the archaeal genomes","volume":"5","author":"Luo","year":"2014","journal-title":"Front. Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2640","DOI":"10.1093\/jac\/dks261","article-title":"Identification of acquired antimicrobial resistance genes","volume":"67","author":"Zankari","year":"2012","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/0042-6822(55)90016-7","article-title":"Transduction of linked genetic characters of the host by bacteriophage P1","volume":"1","author":"Lennox","year":"1955","journal-title":"Virology"}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/9\/6\/296\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:35:02Z","timestamp":1760175302000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/9\/6\/296"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,2]]},"references-count":24,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["antibiotics9060296"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics9060296","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,2]]}}}