Sep. 1, 1998 Discovery, Published In PNAS, Paves Way For New Antibiotic Development
CINCINNATI -- Scientists at Children's Hospital Medical Center of Cincinnati have discovered a major mechanism by which bacteria protect themselves against the human immune response - a discovery that opens the door for development of a new class of antibiotics to fight infection.
In the study, to be published in the September edition of Proceedings of the National Academy of Sciences, the researchers have discovered that flavohemoglobin, a protein in bacteria, protects the bacteria from nitric oxide (NO), a toxic chemical secreted by the immune system to help kill disease-causing microorganisms. The protein, which the researchers have re-named nitric oxide dioxygenase (NOD), detoxifies NO, providing protection against infection.
"It's a breakthrough concept," says Andrew Salzman, M.D., director of critical care at Cincinnati Children's and co-discoverer of the mechanism, along with Paul Gardner, Ph.D, and colleagues in the Kindervelt Shock Research Center at Children's. "With this discovery, Dr. Gardner has created a new field of research."
NO is a toxin produced by inflammatory cells that injures or kills bacteria. Over time, however, a mechanism has evolved that prevents NO from damaging bacteria. This detoxification of NO allows bacteria to survive. Without this protection, they would be unable to infect the host. Interestingly, NOD is an old protein, perhaps billions of years old, originating around the time oxygen appeared in the earth's atmosphere.
"It's actually the forerunner of hemoglobin - a protein in red blood cells that carries oxygen," says Dr. Salzman. "It's abundant and present throughout the animal kingdom for transporting oxygen in the blood. It's been known for many years that there is a form of hemoglobin in bacteria, but its function was entirely unknown. It surely wasn't to carry oxygen. Now we've discovered what we believe is the fundamental purpose of this protein - to protect organisms against nitric oxide. So we are now providing an understanding of the evolutionary basis of hemoglobin and the original function of the hemoglobin family - to detoxify nitric oxide."
This evolutionary history has broad and dramatic implications for human health. Overwhelming infection is one of the major reasons for children and adults are admitted to intensive care units. It's also one of the leading causes of death. New antibiotics could change that.
"Bacteria vary enormously in their ability to defend themselves against nitric oxide," says Dr. Salzman. "But if you remove this protein from bacteria, you can kill them with almost nothing. They're exquisitely sensitive to nitric oxide. Yet, if they're exposed to nitric oxide all the time, the bacteria rev up this system to detoxify it."
Dr. Salzman speculates that this may be what predisposes smokers to infection. Smokers constantly bathe their lungs with huge concentrations of NO. It is possible that bacteria in the lungs of smokers become more resistant to the effects of nitric oxide.
So far, Children's scientists have studied only the most common bacteria at the basic level. But because NOD is broadly represented in different bacteria, they have no reason to believe this mechanism is unique to any particular strain.
Children's Hospital Medical Center of Cincinnati is one of the nation's leading pediatric research institutions, ranking third among comprehensive pediatric research centers in NIH funding. Between 1993 and 1998, National Institutes of Health awards rose from $8 million to $27 million. Investigators have made major contributions to the advancement of pediatric medicine, including the Sabin oral polio vaccine and Survanta, a drug used to treat respiratory distress syndrome that is estimated to save the lives of at least 2,000 infants each year in the United States. Cincinnati Children's vision is "to be the leader in improving child health."
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