{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T17:38:51Z","timestamp":1781977131579,"version":"3.54.5"},"reference-count":46,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T00:00:00Z","timestamp":1675296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006342","name":"Vaincre la Mucoviscidose","doi-asserted-by":"publisher","award":["RF20180502192"],"award-info":[{"award-number":["RF20180502192"]}],"id":[{"id":"10.13039\/501100006342","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006342","name":"Vaincre la Mucoviscidose","doi-asserted-by":"publisher","award":["RF20160501633"],"award-info":[{"award-number":["RF20160501633"]}],"id":[{"id":"10.13039\/501100006342","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Gr\u00e9gory Lemarchal","award":["RF20180502192"],"award-info":[{"award-number":["RF20180502192"]}]},{"name":"Gr\u00e9gory Lemarchal","award":["RF20160501633"],"award-info":[{"award-number":["RF20160501633"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pseudomonas aeruginosa is a major hospital-associated pathogen that can cause severe infections, most notably in patients with cystic fibrosis (CF) or those hospitalized in intensive care units. Given its remarkable ability to resist antibiotics, P. aeruginosa eradication has grown more challenging. Therefore, there is an urgent need to discover and develop new strategies that can counteract P. aeruginosa-resistant strains. Here, we evaluated the efficacy of poly-L-lysine (pLK) in combination with commonly used antibiotics as an alternative treatment option against P. aeruginosa. First, we demonstrated by scanning electron microscopy that pLK alters the integrity of the surface membrane of P. aeruginosa. We also showed using a fluorometry test that this results in an enhanced permeability of the bacteria membrane. Based on these data, we further evaluated the effect of the combinations of pLK with imipenem, ceftazidime, or aztreonam using the broth microdilution method in vitro. We found synergies in terms of bactericidal effects against either sensitive or resistant P. aeruginosa strains, with a reduction in bacterial growth (up to 5-log10 compared to the control). Similarly, these synergistic and bactericidal effects were confirmed ex vivo using a 3D model of human primary bronchial epithelial cells maintained in an air\u2013liquid interface. In conclusion, pLK could be an innovative antipseudomonal molecule, opening its application as an adjuvant antibiotherapy against drug-resistant P. aeruginosa strains.<\/jats:p>","DOI":"10.3390\/ijms24032851","type":"journal-article","created":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T02:57:24Z","timestamp":1675306644000},"page":"2851","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Poly-L-Lysine to Fight Antibiotic Resistances of Pseudomonas aeruginosa"],"prefix":"10.3390","volume":"24","author":[{"given":"Adeline","family":"Cezard","sequence":"first","affiliation":[{"name":"INSERM, Centre d\u2019Etude des Pathologies Respiratoires (CEPR), UMR 1100, 37000 Tours, France"},{"name":"Universit\u00e9 de Tours, Facult\u00e9 de M\u00e9decine, 37000 Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Fouquenet","sequence":"additional","affiliation":[{"name":"INSERM, Centre d\u2019Etude des Pathologies Respiratoires (CEPR), UMR 1100, 37000 Tours, France"},{"name":"Universit\u00e9 de Tours, Facult\u00e9 de M\u00e9decine, 37000 Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Vasseur","sequence":"additional","affiliation":[{"name":"INSERM, Centre d\u2019Etude des Pathologies Respiratoires (CEPR), UMR 1100, 37000 Tours, France"},{"name":"Universit\u00e9 de Tours, Facult\u00e9 de M\u00e9decine, 37000 Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katy","family":"Jeannot","sequence":"additional","affiliation":[{"name":"UMR 6249 Chrono-Environnement, UFR Sciences M\u00e9dicales et Pharmaceutiques, Universit\u00e9 de Bourgogne-Franche Comt\u00e9, 25030 Besan\u00e7on, France"},{"name":"French National Reference Centre for Antibiotic Resistance, 25030 Besan\u00e7on, France"},{"name":"D\u00e9partement de Bact\u00e9riologie, CHU de Besan\u00e7on, 25030 Besan\u00e7on, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabien","family":"Launay","sequence":"additional","affiliation":[{"name":"INSERM, Centre d\u2019Etude des Pathologies Respiratoires (CEPR), UMR 1100, 37000 Tours, France"},{"name":"Universit\u00e9 de Tours, Facult\u00e9 de M\u00e9decine, 37000 Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustapha","family":"Si-Tahar","sequence":"additional","affiliation":[{"name":"INSERM, Centre d\u2019Etude des Pathologies Respiratoires (CEPR), UMR 1100, 37000 Tours, France"},{"name":"Universit\u00e9 de Tours, Facult\u00e9 de M\u00e9decine, 37000 Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9687-0163","authenticated-orcid":false,"given":"Virginie","family":"Herv\u00e9","sequence":"additional","affiliation":[{"name":"INSERM, Centre d\u2019Etude des Pathologies Respiratoires (CEPR), UMR 1100, 37000 Tours, France"},{"name":"Universit\u00e9 de Tours, Facult\u00e9 de M\u00e9decine, 37000 Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,2]]},"reference":[{"key":"ref_1","unstructured":"O\u2019Neill, J. (2016). Tackling Drug-Resistant Infections Globally: Final Report and Recommendations. Review on Antimicrobial Resistance, The Welcome Trust."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e00181-19","DOI":"10.1128\/CMR.00181-19","article-title":"Antimicrobial Resistance in ESKAPE Pathogens","volume":"33","author":"Forde","year":"2020","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1586\/eri.13.12","article-title":"Clinical Relevance of the ESKAPE Pathogens","volume":"11","author":"Pendleton","year":"2013","journal-title":"Expert Rev. Anti-Infect. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1139\/cjm-2015-0536","article-title":"The Characteristics of Genetically Related Pseudomonas Aeruginosa from Diverse Sources and Their Interaction with Human Cell Lines","volume":"62","author":"Streeter","year":"2016","journal-title":"Can. J. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1097\/MCP.0b013e32835f27be","article-title":"Hospital-Acquired Pneumonia and Ventilator-Associated Pneumonia: Recent Advances in Epidemiology and Management","volume":"19","author":"Barbier","year":"2013","journal-title":"Curr. Opin. Pulm. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.addr.2014.10.009","article-title":"Clinical Applications of Pulmonary Delivery of Antibiotics","volume":"85","author":"Flume","year":"2015","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Taccetti, G., Francalanci, M., Pizzamiglio, G., Messore, B., Carnovale, V., Cimino, G., and Cipolli, M. (2021). Cystic Fibrosis: Recent Insights into Inhaled Antibiotic Treatment and Future Perspectives. Antibiotics, 10.","DOI":"10.3390\/antibiotics10030338"},{"key":"ref_8","first-page":"441","article-title":"Impact of Multidrug-Resistant Pseudomonas Aeruginosa Infection on Patient Outcomes","volume":"10","author":"Hirsch","year":"2010","journal-title":"Expert Rev. Pharm. Outcomes Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.1016\/S0140-6736(22)02185-7","article-title":"Global Mortality Associated with 33 Bacterial Pathogens in 2019: A Systematic Analysis for the Global Burden of Disease Study 2019","volume":"400","author":"Ikuta","year":"2022","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.biotechadv.2018.11.013","article-title":"Antibiotic Resistance in Pseudomonas Aeruginosa: Mechanisms and Alternative Therapeutic Strategies","volume":"37","author":"Pang","year":"2019","journal-title":"Biotechnol. Adv."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1128\/AAC.39.9.1948","article-title":"Role of MexA-MexB-OprM in Antibiotic Efflux in Pseudomonas Aeruginosa","volume":"39","author":"Li","year":"1995","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5341","DOI":"10.1128\/JB.187.15.5341-5346.2005","article-title":"Induction of the MexXY Efflux Pump in Pseudomonas Aeruginosa Is Dependent on Drug-Ribosome Interaction","volume":"187","author":"Jeannot","year":"2005","journal-title":"J. Bacteriol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2624","DOI":"10.1128\/AAC.43.11.2624","article-title":"Involvement of an Active Efflux System in the Natural Resistance of Pseudomonas Aeruginosa to Aminoglycosides","volume":"43","author":"Aires","year":"1999","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1128\/CMR.15.2.194-222.2002","article-title":"Lung Infections Associated with Cystic Fibrosis","volume":"15","author":"Lyczak","year":"2002","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/nrmicro2415","article-title":"The Biofilm Matrix","volume":"8","author":"Flemming","year":"2010","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"S63","DOI":"10.1093\/ofid\/ofy343","article-title":"Geographic and Temporal Patterns of Antimicrobial Resistance in Pseudomonas Aeruginosa Over 20 Years from the SENTRY Antimicrobial Surveillance Program, 1997\u20132016","volume":"6","author":"Shortridge","year":"2019","journal-title":"Open Forum Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e02336-22","DOI":"10.1128\/spectrum.02336-22","article-title":"Assessing Rates of Co-Resistance and Patient Outcomes in Multidrug-Resistant Pseudomonas Aeruginosa","volume":"10","author":"Appaneal","year":"2022","journal-title":"Microbiol. Spectr."},{"key":"ref_18","first-page":"960","article-title":"Multir\u00e9sistance Chez Pseudomonas Aeruginosa: Vers l\u2019impasse Th\u00e9rapeutique?","volume":"26","author":"Barbier","year":"2010","journal-title":"Med. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"fnx121","DOI":"10.1093\/femsle\/fnx121","article-title":"Current and Future Therapies for Pseudomonas Aeruginosa Infection in Patients with Cystic Fibrosis","volume":"364","author":"Smith","year":"2017","journal-title":"FEMS Microbiol. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.medmal.2005.10.007","article-title":"Targeting Mechanisms of Pseudomonas Aeruginosa Pathogenesis","volume":"36","author":"Kipnis","year":"2006","journal-title":"M\u00e9decine Mal. Infect."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S146","DOI":"10.1016\/S1569-1993(11)60019-2","article-title":"Antibiotic Treatment of CF Lung Disease: From Bench to Bedside","volume":"10","author":"Bals","year":"2011","journal-title":"J. Cyst. Fibros."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Bellemare, A., Vernoux, N., Morin, S., Gagn\u00e9, S.M., and Bourbonnais, Y. (2010). Structural and Antimicrobial Properties of Human Pre-Elafin\/Trappin-2 and Derived Peptides against Pseudomonas Aeruginosa. BMC Microbiol., 10.","DOI":"10.1186\/1471-2180-10-253"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1164\/rccm.201305-0912OC","article-title":"Poly-l-Lysine Compacts DNA, Kills Bacteria, and Improves Protease Inhibition in Cystic Fibrosis Sputum","volume":"188","author":"Dubois","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e00564-18","DOI":"10.1128\/AAC.00564-18","article-title":"Treatment of Pseudomonas Aeruginosa Biofilm Present in Endotracheal Tubes by Poly-l-Lysine","volume":"62","author":"Guillon","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_25","unstructured":"Pai, M.P., Cottrell, M.L., Kashuba, A.D.M., and Bertino, J.S. (2015). Mandell, Douglas, and Bennett\u2019s Principles and Practice of Infectious Diseases, Elsevier."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1093\/jac\/11.5.427","article-title":"The Fractional Inhibitory Concentration (FIC) Index as a Measure of Synergy","volume":"11","author":"Hall","year":"1983","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"100640","DOI":"10.1016\/j.drup.2019.07.002","article-title":"Antibiotic Resistance in Pseudomonas Aeruginosa\u2014Mechanisms, Epidemiology and Evolution","volume":"44","author":"Botelho","year":"2019","journal-title":"Drug Resist. Updates"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"S50","DOI":"10.1038\/d41586-020-02884-3","article-title":"Why Big Pharma Has Abandoned Antibiotics","volume":"586","author":"Plackett","year":"2020","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e01008-17","DOI":"10.1128\/AAC.01008-17","article-title":"Ceftazidime-Avibactam and Aztreonam, an Interesting Strategy to Overcome \u03b2-Lactam Resistance Conferred by Metallo-\u03b2-Lactamases in Enterobacteriaceae and Pseudomonas Aeruginosa","volume":"61","author":"Davido","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.ijmm.2015.11.004","article-title":"Antibiotic Resistance in Pseudomonas Aeruginosa and Alternative Therapeutic Options","volume":"306","author":"Chatterjee","year":"2016","journal-title":"Int. J. Med. Microbiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"970400","DOI":"10.3389\/fphar.2022.970400","article-title":"Artemisinin Derivative DHA27 Enhances the Antibacterial Effect of Aminoglycosides against Pseudomonas Aeruginosa by Inhibiting MRNA Expression of Aminoglycoside-Modifying Enzymes","volume":"13","author":"Wang","year":"2022","journal-title":"Front. Pharm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e14153","DOI":"10.1111\/jfpp.14153","article-title":"Review of the Application of \u0395-poly-L-lysine in Improving Food Quality and Preservation","volume":"43","author":"Tuersuntuoheti","year":"2019","journal-title":"J. Food Process. Preserv."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.7164\/antibiotics.37.1449","article-title":"Antimicrobial Action of \u03b5-Poly-L-Lysine","volume":"37","author":"Shima","year":"1984","journal-title":"J. Antibiot."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1038\/s41429-022-00523-9","article-title":"Combination Effect of Epsilon-Poly-L-Lysine and Antibiotics against Common Bacterial Pathogens","volume":"75","author":"Sundaran","year":"2022","journal-title":"J. Antibiot."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4225","DOI":"10.12659\/MSM.903145","article-title":"Effects of \u03b5-Polylysine on Pseudomonas Aeruginosa and Aspergillus Fumigatus Biofilm In Vitro","volume":"23","author":"Wei","year":"2017","journal-title":"Med. Sci. Monit."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1271\/bbb.110201","article-title":"Occurrence, Biosynthesis, Biodegradation, and Industrial and Medical Applications of a Naturally Occurring \u03b5-Poly-L-Lysine","volume":"75","author":"Hamano","year":"2011","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8852","DOI":"10.1073\/pnas.1812779115","article-title":"The Bacterial Outer Membrane Is an Evolving Antibiotic Barrier","volume":"115","author":"May","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nrmicro1098","article-title":"Antimicrobial Peptides: Pore Formers or Metabolic Inhibitors in Bacteria?","volume":"3","author":"Brogden","year":"2005","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s00253-003-1312-9","article-title":"??-Poly-l-Lysine: Microbial Production, Biodegradation and Application Potential","volume":"62","author":"Yoshida","year":"2003","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1086\/429323","article-title":"Colistin: The Revival of Polymyxins for the Management of Multidrug-Resistant Gram-Negative Bacterial Infections","volume":"40","author":"Falagas","year":"2005","journal-title":"Clin. Infect. Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1038\/s42003-022-03836-5","article-title":"The Membrane-Active Polyaminoisoprenyl Compound NV716 Re-Sensitizes Pseudomonas Aeruginosa to Antibiotics and Reduces Bacterial Virulence","volume":"5","author":"Wang","year":"2022","journal-title":"Commun. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/s12929-020-00678-3","article-title":"A Synthetic Peptide Sensitizes Multi-Drug Resistant Pseudomonas Aeruginosa to Antibiotics for More than Two Hours and Permeabilizes Its Envelope for Twenty Hours","volume":"27","author":"Shahrour","year":"2020","journal-title":"J. Biomed. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"33","DOI":"10.32607\/20758251-2018-10-4-33-48","article-title":"Bacterial Enzymes and Antibiotic Resistance","volume":"10","author":"Egorov","year":"2018","journal-title":"Acta Nat."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3315","DOI":"10.1021\/bi00713a022","article-title":"Mechanism by Which Cyanine Dyes Measure Membrane Potential in Red Blood Cells and Phosphatidylcholine Vesicles","volume":"13","author":"Sims","year":"1974","journal-title":"Biochemistry"},{"key":"ref_45","unstructured":"(2018). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically (Standard No. M07-A11)."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1016\/S0025-7125(05)70294-7","article-title":"Antibiotic Synergy and Antagonism","volume":"84","author":"Acar","year":"2000","journal-title":"Med. Clin. N. Am."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2851\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:21:47Z","timestamp":1760120507000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2851"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,2]]},"references-count":46,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24032851"],"URL":"https:\/\/doi.org\/10.3390\/ijms24032851","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,2]]}}}