Pseudomonas aeruginosa (PA) is the most common pathogen associated with chronic respiratory disease exacerbations. Host-directed drugs are promising solutions, especially against multi-drug resistant (MDR) strains.

Flagellin (FliC) triggers the immune system through a Toll-like receptor 5 (TLR5)-mechanism. Since TLR5 is widely distributed in the lungs, FliC can be used as a host-directed adjuvant. Here, we evaluate the effect of prophylactic intranasal FliC against a MDR strain of PA (PAMDR) and assess possible synergy with the antibiotic gentamicin (GNT).

Mice were treated intranasally with FliC or PBS 24h before infection with PAMDR strain. 1h post-infection(p.i.) the same mice received, or not, GNT intraperitoneally. Bacterial load, inflammatory markers and lungs' aspect were analysed 16h p.i.. Survival studies were also conducted.

The lungs of mice that received both FliC and GNT did not show signs of inflammation, contrary to the control groups. The same mice also showed significant reduction in bacterial load which could be due to the concomitant increased phagocytes recruitment. Survival studies showed that while GNT alone was not able to improve survival, combination therapy increased mice survival by 100%.

Our results suggest that a preventive nasal administration of FliC restore GNT effect against a MDR strain of P. aeruginosa. Our data may pave the way for the use of FliC in patients with chronic respiratory diseases, who are especially vulnerable to antibiotic-resistant P. aeruginosa infections.

This project (FAIR) has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement Nº847786.