Crippled Antibiotic Linked to Cystic Fibrosis Infections

People with cystic fibrosis are prone to killer lung infections. But scientists have been puzzled over how the genetic defect underlying the disease--a mutated gene that leads to poor transport of chloride into and out of cells--promotes these infections. Now comes a possible explanation: An antibiotic that the lung normally produces is inactivated in a salty environment. The finding, reported in the current issue of the journal Cell, suggests that somehow switching the antibiotic back on--or replacing it with one that can function in salty lung fluid--might reduce the number of fatal infections.

Last year, researchers found that certain strains of bacteria are tamed in low-salt lung fluid of healthy people, but thrive in salty lung fluid of CF patients. Now a team led by James Wilson of the Institute for Human Gene Therapy in Philadelphia and Michael Zasloff of the Magainin Research Institute in Plymouth Meeting, Pennsylvania, appear to have found what sets these lung fluids apart. They discovered in human lung cells messenger RNA that helps make a protein called human beta-defensin, first isolated from kidney dialysis fluid a few years ago.

In the presence of low-salt fluid, they found, a synthetic version of human beta-defensin was a potent weapon against a broad range of bacteria, including P. aeroginosa and E. coli, two bugs that plague people with cystic fibrosis. But when exposed to high salt levels, the human beta-defensin was practically powerless. "It helps bridge that gap about how a defect in an ion channel leads to defects in the lungs," says Magainin institute molecular biologist Mark Anderson.

Not everyone is convinced that all cystic fibrosis sufferers have salty lung fluid. Nevertheless, experts are hailing the finding. "It's very exciting," says Charles Bevins of the Cleveland Clinic, who helped isolate beta-defensins from the cow trachea and gastrointestinal tract. Bevins says that human
beta-defensin might be used as a drug to fight cystic fibrosis lung infections if researchers are able to modify it to withstand high salt levels. More likely drug candidates, he says, are protegrin, a compound isolated from pig neutrophils, or microbial peptides called the magainins, first isolated 10 years ago from frog skin, some of which would fare better than defensins in salty solutions.

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