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Previous works in vitro showed that peptidoglycan recycling blockade disables AmpC-dependent resistance and enhances susceptibility against cell-wall\u2013targeting immunity. Our objective was to validate these findings in murine models.<\/jats:p>\n                  <jats:p>This study shows for the first time in different murine models of infection that blocking the peptidoglycan recycling in Pseudomonas aeruginosa causes an important virulence impairment and disables AmpC-mediated resistance, being hence validated as a promising therapeutic target.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Wildtype PAO1, recycling-defective AmpG and NagZ mutants, an AmpC hyperproducer dacB mutant, and their combinations were used to cause systemic\/respiratory infections in mice. Their survival, bacterial burden, inflammation level, and effectiveness of ceftazidime or subtherapeutic colistin to treat the infections were assessed.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Inactivation of AmpG or NagZ significantly attenuated the virulence in terms of mice mortality, bacterial load, and inflammation. When inactivating these genes in the dacB-defective background, the \u03b2-lactam resistance phenotype was abolished, disabling the emergence of ceftazidime-resistant mutants, and restoring ceftazidime for treatment. Subtherapeutic colistin was shown to efficiently clear the infection caused by the recycling-defective strains, likely due to the combined effect with the mice cell-wall\u2013 targeting immunity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This study brings us one step closer to new therapies intended to disable P. aeruginosa AmpC-mediated resistance and dampen its virulence, and strongly support the interest in developing efficient AmpG and\/or NagZ inhibitors.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/infdis\/jiz377","type":"journal-article","created":{"date-parts":[[2019,7,16]],"date-time":"2019-07-16T15:11:22Z","timestamp":1563289882000},"page":"1729-1737","source":"Crossref","is-referenced-by-count":17,"title":["In Vivo Validation of Peptidoglycan Recycling as a Target to Disable AmpC-Mediated Resistance and Reduce Virulence Enhancing the Cell-Wall\u2013Targeting Immunity"],"prefix":"10.1093","volume":"220","author":[{"given":"Gabriel","family":"Torrens","sequence":"first","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n, Hospital Son Espases, Instituto de Investigaci\u00f3n Sanitaria de Baleares, Palma, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"S\u00e1nchez-Diener","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n, Hospital Son Espases, Instituto de Investigaci\u00f3n Sanitaria de Baleares, Palma, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Jordana-Lluch","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n, Hospital Son Espases, Instituto de Investigaci\u00f3n Sanitaria de Baleares, Palma, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel Mar\u00eda","family":"Barcel\u00f3","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n, Hospital Son Espases, Instituto de Investigaci\u00f3n Sanitaria de Baleares, Palma, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Zamorano","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n, Hospital Son Espases, Instituto de Investigaci\u00f3n Sanitaria de Baleares, Palma, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Juan","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n, Hospital Son Espases, Instituto de Investigaci\u00f3n Sanitaria de Baleares, Palma, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1402-3516","authenticated-orcid":false,"given":"Antonio","family":"Oliver","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n, Hospital Son Espases, Instituto de Investigaci\u00f3n Sanitaria de Baleares, Palma, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,7,20]]},"reference":[{"key":"2019102207591598300_CIT0001","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.12688\/f1000research.10506.1","article-title":"Recent advances in understanding Pseudomonas aeruginosa as a pathogen","volume":"6","author":"Klockgether","year":"2017","journal-title":"F1000Res"},{"key":"2019102207591598300_CIT0002","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.1016\/S0140-6736(03)13644-6","article-title":"Nosocomial infections in adult intensive-care 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