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    Genome expression profiling-based identification and administration efficacy of host-directed antimicrobial drugs against respiratory infection by nontypeable Haemophilus influenzae

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    Date
    2015
    Author
    Euba, Begoña 
    Moleres Apilluelo, Javier 
    Segura, Víctor 
    Viadas Martínez, Cristina Upna
    Morey Sancho, Pau 
    Moranta, David 
    Leiva, José 
    Torres, Juan de 
    Bengoechea Alonso, José Antonio 
    Garmendia García, Juncal 
    Version
    Acceso abierto / Sarbide irekia
    xmlui.dri2xhtml.METS-1.0.item-type
    Artículo / Artikulua
    Version
    Versión publicada / Argitaratu den bertsioa
    Project Identifier
    ES/6PN/SAF2012-31166 
    Impact
     
     
     
    10.1128/aac.01278-15
     
     
     
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    Abstract
    Therapies 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 effic ... [++]
    Therapies 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. [--]
    Subject
    Nontypeable Haemophilus influenzae (NTHi), Host-directed antimicrobial drugs
     
    Publisher
    American Society for Microbiology
    Published in
    Antimicrobial Agents and Chemotherapy, 9:7581–7592
    Departament
    IdAB – Instituto de Agrobiotecnología / Agrobioteknologiako Institutua
    Publisher version
    https://doi.org/10.1128/aac.01278-15
    URI
    https://hdl.handle.net/2454/31928
    Sponsorship
    J.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.
    Appears in Collections
    • Artículos de revista IdAB - IdAB Aldizkari artikuluak [159]
    • Artículos de revista - Aldizkari artikuluak [2168]
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