The development of
therapies that modulate or prevent pathogen virulence may be a key strategy for circumventing antimicrobial resistance. Toward that end, we examined the production of
pyoverdine, a key virulence determinant, in ∼70 Pseudomonas aeruginosa isolates from pediatric
cystic fibrosis patients.
Pyoverdine production was heterogeneous and showed a clear correlation with pathogenicity in Caenorhabditis elegans and an acute murine
pneumonia model. Examination showed
pyoverdine accumulation in host tissues, including extrapharyngeal tissues of C. elegans and lung tissues of mice, where accumulation correlated with host death. Many of the isolates tested were resistant to multiple antimicrobials, so we assayed the ability of
pyoverdine inhibitors to mitigate virulence and rescue
pyoverdine-mediated host pathology. Representatives from three different classes of
pyoverdine inhibitors (
gallium, fluoropyrimidines, and LK11) significantly improved survival. Our findings highlight the utility of targeting
virulence factors in general, and
pyoverdine in particular, as a promising method to control bacterial pathogenesis as the utility of antimicrobials continues to diminish.