New Drugs for CF Bugs: testing anti-virulence therapies against Pseudomonas aeruginosa in Cystic Fibrosis

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Cystic Fibrosis (CF) is the most prevalent autosomal recessive disease amongst the Caucasian population. CF is a multisystemic disorder, causing an array of clinical symptoms, however, progressive lung disease is the main cause of morbidity and mortality rates in individuals diagnosed with the disorder. Of the bacteria comprising these infections, Pseudomonas aeruginosa (Pa) most commonly presents to clinical practise, and thus, represents a significant risk to patients diagnosed with CF. Antibiotic resistance (AMR) symbolizes a major global health threat, with the WHO placing Pa as a priority pathogen that desperately requires new treatment strategies. CF patients are regularly treated with aggressive antibiotic therapy, particularly during periodic pulmonary exacerbations. The development of anti-virulence therapeutics may provide a clinically effective means of treating Pa lung infections whilst also combatting the AMR crisis. However, due to its complex polymicrobial environment, it is difficult to replicate the conditions of the CF lung within in vitro models. This poses challenges when screening novel antimicrobial agents, as results obtained in simple laboratory media do not often reflect drug activity in vivo. Such challenges are exacerbated when screening anti-virulence drugs, as standard microbiological endpoints that measure bacterial density or viability do not provide an understanding of host-pathogen interactions. The utilisation of an array of in vitro assays including artificial sputum models and phenotypic assays, and in vivo zebrafish models may be key in the analysis of significant Pa virulence factors and the subsequent development of effective anti-virulence therapies.