Impact of Type III Secretion Effectors and of Phenoxyacetamide Inhibitors of Type III Secretion on Abscess Formation in a Mouse Model of Pseudomonas aeruginosa Infection

Abstract

<i>Pseudomonas aeruginosa</i> is a leading cause of intra-abdominal infections, wound infections, and community-acquired folliculitis, each of which may involve macro- or microabscess formation. The rising incidence of multidrug resistance among <i>P. aeruginosa</i> isolates has increased both the economic burden and the morbidity and mortality associated with <i>P. aeruginosa</i> disease and necessitates a search for novel therapeutics. Previous work from our group detailed novel phenoxyacetamide inhibitors that block type III secretion and injection into host cells <i>in vitro</i> In this study, we used a mouse model of <i>P. aeruginosa</i> abscess formation to test the <i>in vivo</i> efficacy of these compounds against the <i>P. aeruginosa</i> type III secretion system (T3SS). Bacteria used the T3SS to intoxicate infiltrating neutrophils to establish abscesses. Despite this antagonism, sufficient numbers of functioning neutrophils remained for proper containment of the abscesses, as neutrophil depletion resulted in an increased abscess size, the formation of dermonecrotic lesions on the skin, and the dissemination of <i>P. aeruginosa</i> to internal organs. Consistent with the specificity of the T3SS-neutrophil interaction, <i>P. aeruginosa</i> bacteria lacking a functional T3SS were fully capable of causing abscesses in a neutropenic host. Phenoxyacetamide inhibitors attenuated abscess formation and aided in the immune clearance of the bacteria. Finally, a <i>P. aeruginosa</i> strain resistant to the phenoxyacetamide compound was fully capable of causing abscess formation even in the presence of the T3SS inhibitors. Together, our results further define the role of type III secretion in murine abscess formation and demonstrate the <i>in vivo</i> efficacy of phenoxyacetamide inhibitors in <i>P. aeruginosa</i> infection.