(American Society for Microbiology, 2015) Euba, Begoña; Moleres Apilluelo, Javier; Segura, Víctor; Viadas Martínez, Cristina; Morey Sancho, Pau; Moranta, David; Leiva, José; Torres, Juan de; Bengoechea Alonso, José Antonio; Garmendia García, Juncal; IdAB. Instituto de Agrobiotecnología / Agrobioteknologiako Institutua; Gobierno de Navarra / Nafarroako Gobernua
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.
