| Summary: | The opportunistic human pathogen <i>Pseudomonas aeruginosa</i> is responsible for a variety of acute infections and is a major cause of mortality in chronically infected cystic fibrosis patients. Due to increased resistance to antibiotics, new therapeutic strategies against <i>P. aeruginosa</i> are urgently needed. In this context, we aimed to develop a simple vertebrate animal model to rapidly assess in vivo drug efficacy against <i>P. aeruginosa</i>. Zebrafish are increasingly considered for modeling human infections caused by bacterial pathogens, which are commonly microinjected in embryos. In the present study, we established a novel protocol for zebrafish infection by <i>P. aeruginosa</i> based on bath immersion in 96-well plates of tail-injured embryos. The immersion method, followed by a 48-hour survey of embryo viability, was first validated to assess the virulence of <i>P. aeruginosa</i> wild-type PAO1 and a known attenuated mutant. We then validated its relevance for antipseudomonal drug testing by first using a clinically used antibiotic, ciprofloxacin. Secondly, we used a novel quorum sensing (QS) inhibitory molecule, <i>N</i>-(2-pyrimidyl)butanamide (C11), the activity of which had been validated in vitro but not previously tested in any animal model. A significant protective effect of C11 was observed on infected embryos, supporting the ability of C11 to attenuate in vivo <i>P. aeruginosa</i> pathogenicity. In conclusion, we present here a new and reliable method to compare the virulence of <i>P. aeruginosa</i> strains in vivo and to rapidly assess the efficacy of clinically relevant drugs against <i>P. aeruginosa</i>, including new antivirulence compounds.
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