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dc.creatorEuba, Begoñaes_ES
dc.creatorMoleres Apilluelo, Javieres_ES
dc.creatorSegura, Víctores_ES
dc.creatorViadas Martínez, Cristinaes_ES
dc.creatorMorey Sancho, Paues_ES
dc.creatorMoranta, Davides_ES
dc.creatorLeiva, Josées_ES
dc.creatorTorres, Juan dees_ES
dc.creatorBengoechea Alonso, José Antonioes_ES
dc.creatorGarmendia García, Juncales_ES
dc.date.accessioned2019-01-10T08:27:50Z
dc.date.available2019-01-10T08:27:50Z
dc.date.issued2015
dc.identifier.issn0066-4804 (Print)
dc.identifier.issn1098-6596 (Electronic)
dc.identifier.urihttps://hdl.handle.net/2454/31928
dc.description.abstractTherapies that are safe, effective, and not vulnerable to developing resistance are highly desirable to counteract bacterial infections. Host-directed therapeutics is an antimicrobial approach alternative to conventional antibiotics based on perturbing host pathways subverted by pathogens during their life cycle by using host-directed drugs. In this study, we identified and evaluated the efficacy of a panel of host-directed drugs against respiratory infection by nontypeable Haemophilus influenzae (NTHi). NTHi is an opportunistic pathogen that is an important cause of exacerbation of chronic obstructive pulmonary disease (COPD). We screened for host genes differentially expressed upon infection by the clinical isolate NTHi375 by analyzing cell whole-genome expression profiling and identified a repertoire of host target candidates that were pharmacologically modulated. Based on the proposed relationship between NTHi intracellular location and persistence, we hypothesized that drugs perturbing host pathways used by NTHi to enter epithelial cells could have antimicrobial potential against NTHi infection. Interfering drugs were tested for their effects on bacterial and cellular viability, on NTHi-epithelial cell interplay, and on mouse pulmonary infection. Glucocorticoids and statins lacked in vitro and/or in vivo efficacy. Conversely, the sirtuin-1 activator resveratrol showed a bactericidal effect against NTHi, and the PDE4 inhibitor rolipram showed therapeutic efficacy by lowering NTHi375 counts intracellularly and in the lungs of infected mice. PDE4 inhibition is currently prescribed in COPD, and resveratrol is an attractive geroprotector for COPD treatment. Together, these results expand our knowledge of NTHi-triggered host subversion and frame the antimicrobial potential of rolipram and resveratrol against NTHi respiratory infection.en
dc.description.sponsorshipJ.M. is funded by Ph.D. studentship BES-2013-062644 from the Ministerio Economía y Competitividad-MINECO, Spain. This study was funded by grants from ISCIII (PS09/00130), the Ministerio Economía y Competitividad (MINECO SAF2012-31166), and the Departamento de Salud Gobierno Navarra (359/2012) to J.G.en
dc.format.extent12 p.
dc.format.mimetypeapplication/pdfen
dc.format.mimetypeapplication/zipen
dc.language.isoengen
dc.publisherAmerican Society for Microbiologyen
dc.relation.ispartofAntimicrobial Agents and Chemotherapy, 9:7581–7592en
dc.rights© 2015, American Society for Microbiology. All Rights Reserved.en
dc.subjectNontypeable Haemophilus influenzae (NTHi)en
dc.subjectHost-directed antimicrobial drugsen
dc.titleGenome expression profiling-based identification and administration efficacy of host-directed antimicrobial drugs against respiratory infection by nontypeable Haemophilus influenzaeen
dc.typeinfo:eu-repo/semantics/articleen
dc.typeArtículo / Artikuluaes
dc.contributor.departmentIdAB – Instituto de Agrobiotecnología / Agrobioteknologiako Institutuaes
dc.rights.accessRightsinfo:eu-repo/semantics/openAccessen
dc.rights.accessRightsAcceso abierto / Sarbide irekiaes
dc.identifier.doi10.1128/aac.01278-15
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/6PN/SAF2012-31166
dc.relation.publisherversionhttps://doi.org/10.1128/aac.01278-15
dc.type.versioninfo:eu-repo/semantics/publishedVersionen
dc.type.versionVersión publicada / Argitaratu den bertsioaes
dc.contributor.funderGobierno de Navarra / Nafarroako Gobernuaes


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