Genome Expression Profiling-Based Identification and Administration Efficacy of Host-Directed Antimicrobial Drugs against Respiratory Infection by Nontypeable Haemophilus influenzae
Euba B (1), Moleres J (2), Segura V (3), Viadas C (2), Morey P (4), Moranta D (5), Leiva J (6), de-Torres JP (7), Bengoechea JA (8), Garmendia J (9).
(1) Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, CIBERES, Madrid, Spain Instituto de Agrobiotecnología, CSIC-Universidad Pública Navarra-Gobierno Navarra, Mutilva, Spain.
(2) Instituto de Agrobiotecnología, CSIC-Universidad Pública Navarra-Gobierno Navarra, Mutilva, Spain.
(3) Centro Investigación Médica Aplicada, Universidad de Navarra, Pamplona, Spain.
(4) Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
(5) Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, CIBERES, Madrid, Spain Programme Infection and Immunity, Fundación de Investigación Sanitaria de las Islas Baleares-Instituto de Investigación Sanitaria de Palma, Mallorca, Spain.
(6) Servicio de Microbiología, Clínica Univesidad de Navarra, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.
(7) Servicio de Neumología, Clínica Universidad de Navarra, Pamplona, Spain.
(8) Centre for Infection and Immunity, Queen's University, Belfast, United Kingdom Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
(9) Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, CIBERES, Madrid, Spain Instituto de Agrobiotecnología, CSIC-Universidad Pública Navarra-Gobierno Navarra, Mutilva, Spain
Magazine: Antimicrobial agents and Chemotherapy
Date: Dec 1, 2015Pneumology Clinical Microbiology [SP]
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.
CITATION Antimicrob Agents Chemother. 2015 Dec;59(12):7581-92. doi: 10.1128/AAC.01278-15. Epub 2015 Sep 28.
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