{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:30:12Z","timestamp":1785407412288,"version":"3.56.0"},"reference-count":30,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T00:00:00Z","timestamp":1776470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PMP22\/00092"],"award-info":[{"award-number":["PMP22\/00092"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CB21\/13\/00084"],"award-info":[{"award-number":["CB21\/13\/00084"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI22\/01045"],"award-info":[{"award-number":["PI22\/01045"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"award":["PMP22\/00092"],"award-info":[{"award-number":["PMP22\/00092"]}],"id":[{"id":"https:\/\/ror.org\/00ca2c886","id-type":"ROR","asserted-by":"publisher"}]},{"award":["CB21\/13\/00084"],"award-info":[{"award-number":["CB21\/13\/00084"]}],"id":[{"id":"https:\/\/ror.org\/00ca2c886","id-type":"ROR","asserted-by":"publisher"}]},{"award":["PI22\/01045"],"award-info":[{"award-number":["PI22\/01045"]}],"id":[{"id":"https:\/\/ror.org\/00ca2c886","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF17OC0025074"],"award-info":[{"award-number":["NNF17OC0025074"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"award":["NNF17OC0025074"],"award-info":[{"award-number":["NNF17OC0025074"]}],"id":[{"id":"https:\/\/ror.org\/04txyc737","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Fundaci\u00f3n para la investigaci\u00f3n Biom\u00e9dica del Hospital Universitario Ram\u00f3n y Cajal","award":["IMP23_C10"],"award-info":[{"award-number":["IMP23_C10"]}]},{"name":"Fundaci\u00f3n para la investigaci\u00f3n Biom\u00e9dica del Hospital Universitario Ram\u00f3n y Cajal","award":["IMP19_10"],"award-info":[{"award-number":["IMP19_10"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Background: We aimed to investigate the potential synergistic effect of ivacaftor combined with colistin against Pseudomonas aeruginosa and Klebsiella pneumoniae, and to elucidate the underlying molecular mechanisms through metabolomic analysis and its reproducibility in a murine model. Methods: Six colistin-susceptible and 2 colistin-resistant cystic fibrosis P. aeruginosa isolates, along with two colistin-resistant K. pneumoniae clinical isolates, were studied. Antimicrobial susceptibility was assessed by broth microdilution, and synergy by checkerboard assay. Metabolomic profiling was conducted via LC-HRMS with statistical analysis. A murine pneumonia model, induced by intranasal administration of colistin-resistant strains, was used to validate in vivo ivacaftor and colistin synergy after 24 h. Results: No previously described colistin resistance mutations were identified in P. aeruginosa strains, whereas K. pneumoniae carried mgrB variations. Ivacaftor restored colistin susceptibility at 16 mg\/L concentration, and at 1\u20132 mg\/L led to at least a twofold reduction in colistin MIC. Metabolomic analysis of colistin-resistant P. aeruginosa strains revealed that ivacaftor induced modifications in phosphoethanolamine groups of lipid A. However, no synergistic effects were observed in the short-term in vivo pneumonia model, regardless of the administration route. Conclusions: Ivacaftor exhibited no direct antimicrobial activity against P. aeruginosa and K. pneumoniae isolates in vitro but restored colistin susceptibility through synergistic interactions. The lack of synergy in the murine pneumonia model may reflect treatment time and challenges in standardizing in vivo conditions. These findings highlight the potential of ivacaftor as an adjunct to colistin therapy, warranting further investigation into its clinical applicability.<\/jats:p>","DOI":"10.3390\/antibiotics15040414","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T09:37:42Z","timestamp":1776677862000},"page":"414","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In Vitro Restoration of Colistin Susceptibility by Ivacaftor Synergy with Limited Reproducibility in a Murine Pneumonia Model"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3652-7915","authenticated-orcid":false,"given":"Ana Ver\u00f3nica","family":"Halperin","sequence":"first","affiliation":[{"name":"Servicio de Microbiologia, Hospital Universitario Ram\u00f3n y Cajal and Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology, Copenhagen University Hospital, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Christophersen","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology, Copenhagen University Hospital, 2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"P\u00e9rez-del Palacio","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n MEDINA, Centro de Excelencia en Investigaci\u00f3n de Medicamentos Innovadores en Andaluc\u00eda, Armilla, 18016 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3239-9373","authenticated-orcid":false,"given":"Manuel","family":"Ponce-Alonso","sequence":"additional","affiliation":[{"name":"Servicio de Microbiologia, Hospital Universitario Ram\u00f3n y Cajal and Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"},{"name":"CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2774-1821","authenticated-orcid":false,"given":"Jos\u00e9","family":"Avenda\u00f1o-Ortiz","sequence":"additional","affiliation":[{"name":"Servicio de Microbiologia, Hospital Universitario Ram\u00f3n y Cajal and Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"},{"name":"CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan de Dios","family":"Caballero","sequence":"additional","affiliation":[{"name":"Servicio de Microbiologia, Hospital Universitario Ram\u00f3n y Cajal and Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1675-3173","authenticated-orcid":false,"given":"Rafael","family":"Cant\u00f3n","sequence":"additional","affiliation":[{"name":"Servicio de Microbiologia, Hospital Universitario Ram\u00f3n y Cajal and Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"},{"name":"CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claus","family":"Moser","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology, Copenhagen University Hospital, 2100 Copenhagen, Denmark"},{"name":"Department of Immunology and Microbiology, Copenhagen University, 2200 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1147-7923","authenticated-orcid":false,"given":"Rosa","family":"del Campo","sequence":"additional","affiliation":[{"name":"CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Facultad de Ciencias de la Salud, Universidad de La Rioja, 26006 Logro\u00f1o, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102239","DOI":"10.1016\/j.coph.2022.102239","article-title":"Current state of CFTR modulators for treatment of cystic fibrosis","volume":"65","author":"Despotes","year":"2022","journal-title":"Curr. 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