Genome Expression Profiling-Based Identification and Administration Efficacy of Host-Directed Antimicrobial Drugs against Respiratory Infection by Nontypeable Haemophilus influenzae

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 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.

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

“…The use of host-directed agents for the treatment of antibioticresistant bacteria has recently garnered much attention (5,54,55). Additionally, the repurposing of FDA-approved drugs offers the advantage of readily moving in vitro candidates to in vivo models, since the LD 50 and 50% effective dose (ED 50 ) values are readily available and considerable information about their molecular targets and host pathway interactions is known.…”

Moonlighting of Haemophilus influenzae heme acquisition systems contributes to the host airway-pathogen interplay in a coordinated manner

“…S7B). Last, we used an in vivo mouse respiratory infection model system [79][80][81]85,86]. At 24 hpi, NTHi375ΔhxuCBA lung and BALF bacterial numbers were lower than those recovered for the WT strain ( Figure 6(c), left panels).…”

“…A549 type II human pneumocytes (ATCC CCL-185) were maintained and seeded as described [79][80][81][82][83][84][85][86]. For infection, PBS-normalized bacterial suspensions (OD 600 = 1) were prepared by using NTHi strains grown on chocolate agar.…”

Preclinical Evaluation of the Antimicrobial-Immunomodulatory Dual Action of Xenohormetic Molecules against Haemophilus influenzae Respiratory Infection

“…Quercetin is known to modulate eukaryotic cell signaling by inhibiting Akt phosphorylation [50] and phosphodiesterase 4 (PDE4) [51]. Akt phosphorylation has been reported to facilitate-and increased intracellular cAMP to reduce NTHi epithelial invasion, respectively [39,41,52]. Based on previously known quercetin modulatory effects, we hypothesized that host cell treatment with this polyphenol may reduce NTHi epithelial infection.…”