Genome expression profiling-based identification and administration efficacy of host-directed antimicrobial drugs against respiratory infection by nontypeable Haemophilus influenzae
Fecha
2015Autor
Versión
Acceso abierto / Sarbide irekia
Tipo
Artículo / Artikulua
Versión
Versión publicada / Argitaratu den bertsioa
Impacto
|
10.1128/aac.01278-15
Resumen
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. [--]
Materias
Nontypeable Haemophilus influenzae (NTHi),
Host-directed antimicrobial drugs
Editor
American Society for Microbiology
Publicado en
Antimicrobial Agents and Chemotherapy, 9:7581–7592
Departamento
Universidad Pública de Navarra/Nafarroako Unibertsitate Publikoa. IdAB. Instituto de Agrobiotecnología / Agrobioteknologiako Institutua
Versión del editor
Entidades Financiadoras
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.