{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T14:45:36Z","timestamp":1760453136065,"version":"3.37.3"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T00:00:00Z","timestamp":1646265600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,4,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To search for new means of combatting carbapenemase-producing strains of Klebsiella pneumoniae by repurposing the anti-helminth drug niclosamide as an antimicrobial agent and combining it with the efflux pump inhibitor (EPI) phenyl-arginine-\u03b2-naphthylamide (Pa\u03b2N).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Niclosamide and Pa\u03b2N MICs were determined for six clinical K. pneumoniae isolates harbouring different carbapenemases by broth microdilution and chequerboard assays. Time\u2013kill curves in the presence of each drug alone and in combination were conducted. The viability of bacterial cells in the presence of repetitive exposures at 8\u2005h to the treatment at the same concentration of niclosamide and\/or Pa\u03b2N (adapted isolates) was determined. The acrAB-tolC genes and their regulators were sequenced and quantitative RT\u2013PCR was performed to assess whether the acrA gene was overexpressed in adapted isolates compared with non-adapted isolates. Finally, the MICs of several antimicrobials were determined for the adapted isolates.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Niclosamide and Pa\u03b2N had synergistic effects on the six isolates in vitro, but adaptation appeared when the treatment was applied to the medium every 8\u2005h, with an increase of 6- to 12-fold in the MIC of Pa\u03b2N. Sequencing revealed different mutations in the regulators of the tripartite AcrAB-TolC efflux pump (ramR and acrR) that may be responsible for the overexpression of the efflux pump and the adaptation to this combination. Co-resistance to different antimicrobials confirmed the overexpression of the AcrAB-TolC efflux pump.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Despite the synergistic effect that preliminary in vitro stages may suggest, the combinations of drugs and EPI may generate adapted phenotypes associated with antimicrobial resistance that must be taken into consideration.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkac044","type":"journal-article","created":{"date-parts":[[2022,2,7]],"date-time":"2022-02-07T20:11:52Z","timestamp":1644264712000},"page":"1272-1281","source":"Crossref","is-referenced-by-count":14,"title":["Adaptation of clinical isolates of <i>Klebsiella pneumoniae<\/i> to the combination of niclosamide with the efflux pump inhibitor phenyl-arginine-\u03b2-naphthylamide (Pa\u03b2N): co-resistance to antimicrobials"],"prefix":"10.1093","volume":"77","author":[{"given":"Olga","family":"Pacios","sequence":"first","affiliation":[{"name":"Microbiology Department-Research Institute Biomedical A Coru\u00f1a (INIBIC), Hospital A Coru\u00f1a (CHUAC), University of A Coru\u00f1a (UDC), A Coru\u00f1a, Spain"},{"name":"Study Group on Mechanisms of Action and Resistance to Antimicrobials (GEMARA) on behalf of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Fern\u00e1ndez-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Microbiology Department-Research Institute Biomedical A Coru\u00f1a (INIBIC), Hospital A Coru\u00f1a (CHUAC), University of A Coru\u00f1a (UDC), A Coru\u00f1a, Spain"},{"name":"Study Group on Mechanisms of Action and Resistance to Antimicrobials (GEMARA) on behalf of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"In\u00e9s","family":"Bleriot","sequence":"additional","affiliation":[{"name":"Microbiology Department-Research Institute Biomedical A Coru\u00f1a (INIBIC), Hospital A Coru\u00f1a (CHUAC), University of A Coru\u00f1a (UDC), A Coru\u00f1a, Spain"},{"name":"Study Group on Mechanisms of Action and Resistance to Antimicrobials (GEMARA) on behalf of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"Blasco","sequence":"additional","affiliation":[{"name":"Microbiology Department-Research Institute Biomedical A Coru\u00f1a (INIBIC), Hospital A Coru\u00f1a (CHUAC), University of A Coru\u00f1a (UDC), A Coru\u00f1a, Spain"},{"name":"Study Group on Mechanisms of Action and Resistance to Antimicrobials (GEMARA) on behalf of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ant\u00f3n","family":"Ambroa","sequence":"additional","affiliation":[{"name":"Microbiology Department-Research Institute Biomedical A Coru\u00f1a (INIBIC), Hospital A Coru\u00f1a (CHUAC), University of A Coru\u00f1a (UDC), A Coru\u00f1a, Spain"},{"name":"Study Group on Mechanisms of Action and Resistance to Antimicrobials (GEMARA) on behalf of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"Microbiology Department-Research Institute Biomedical A Coru\u00f1a (INIBIC), Hospital A Coru\u00f1a (CHUAC), University of A Coru\u00f1a (UDC), A Coru\u00f1a, Spain"},{"name":"Study Group on Mechanisms of Action and Resistance to Antimicrobials (GEMARA) on behalf of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC)"},{"name":"Spanish Network for Research in Infectious Diseases (REIPI) and CIBER de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Concha","family":"Ortiz-Cartagena","sequence":"additional","affiliation":[{"name":"Microbiology Department-Research Institute Biomedical A Coru\u00f1a (INIBIC), Hospital A Coru\u00f1a (CHUAC), University of A Coru\u00f1a (UDC), A Coru\u00f1a, Spain"},{"name":"Study Group on Mechanisms of Action and Resistance to Antimicrobials (GEMARA) on behalf of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"Gonz\u00e1lez de Aledo","sequence":"additional","affiliation":[{"name":"Microbiology Department-Research Institute Biomedical A Coru\u00f1a (INIBIC), Hospital A Coru\u00f1a (CHUAC), University of A Coru\u00f1a (UDC), A Coru\u00f1a, 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