Opportunistic pathogens exploit diverse strategies to sabotage host defenses.
Pseudomonas aeruginosa secretes the CFTR inhibitory factor Cif and thus triggers
loss of CFTR, an ion channel required for airway mucociliary defense. However,
the mechanism of action of Cif has remained unclear. It catalyzes epoxide
hydrolysis, but there is no known role for natural epoxides in CFTR regulation.
It was demonstrated that the hydrolase activity of Cif is strictly required for
its effects on CFTR. A small-molecule inhibitor that protects this key component
of the mucociliary defense system was also uncovered. These results provide a
basis for targeting the distinctive virulence chemistry of Cif and suggest an
unanticipated role of physiological epoxides in intracellular protein
trafficking.
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