Human targets of Pseudomonas aeruginosa pyocyanin.
Pseudomonas aeruginosa produces copious amounts of the redoxactive tricyclic compound pyocyanin that kills competing microbes and mammalian cells, especially during cystic fibrosis lung infection. Cross-phylum susceptibility to pyocyanin suggests the existence of evolutionarily conserved physiological targets. We screened a Saccharomyces cerevisiae deletion library to identify presumptive pyocyanin targets with the expectation that similar targets would be conserved in humans. Fifty S. cerevisiae targets were provisionally identified, of which 60% have orthologous human counterparts. These targets encompassed major cellular pathways involved in the cell cycle, electron transport and respiration, epidermal cell growth, protein sorting, vesicle transport, and the vacuolar ATPase. Using cultured human lung epithelial cells, we showed that pyocyanin-mediated reactive oxygen intermediates inactivate human vacuolar ATPase, supporting the validity of the yeast screen. We discuss how the inactivation of V-ATPase may negatively impact the lung function of cystic fibrosis patients.
Ran
Huimin
H
Division of Pulmonary and Critical Care Medicine, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0564, USA.
Hassett
Daniel J
DJ
Lau
Gee W
GW
D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D025141:Drug Resistance, Fungal; D004579:Electron Transport / Q000187:drug effects; D005798:Genes, Bacterial; D005800:Genes, Fungal / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D018384:Oxidative Stress / Q000187:drug effects; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity*; D011710:Pyocyanine / Q000633:toxicity*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism
D011710:Pyocyanine; D025262:Vacuolar Proton-Translocating ATPases