THURSDAY, April 18, 2002 (HealthDayNews) -- The bacteria that frequently infect the lungs of people with cystic fibrosis appear to sidestep antibiotics by temporarily switching to stronger, altered states.
Fortunately, scientists at Harvard Medical School have identified the protein that may regulate this shift into a resistant form, raising the possibility of future therapies to switch the bacteria back to a vulnerable form.
One expert says that while such a treatment is still years away, these findings could ultimately create a chink in Pseudomonas aeruginosa's armor, leaving it susceptible to treatment and improving the lives of people with the disease.
The findings appear in today's issue of Nature.
Cystic fibrosis (CF) is a chronic, progressive and frequently fatal genetic disease of the body's mucus glands that affects roughly 30,000 Americans. The disease causes the body to produce abnormally thick mucus that interferes with the lungs and pancreas. People with CF have a life span of roughly 30 years.
Individuals with this disease are prone to lung infections with P. aeruginosa. The bacteria frequently form thin, antibiotic-resistant sheets, or biofilms.
This latest study unifies two notions about how bacteria in the lungs of people with CF become resistant to antibiotics: that antibiotics select for resistant bacteria; and that biofilms are more resistant than freely existing bacteria.
This study suggests this shifting makes the bacteria both more resistant to antibiotics and more likely to form biofilms.
Senior investigator Frederick Ausubel, a professor of genetics at Harvard, began the study after noticing that when the bacteria was cultured on antibiotic growth media, antibiotic-resistant colonies appeared much faster than expected. Moreover, the colonies were resistant to multiple drugs.
When Ausubel and his colleague, post-doctoral researcher Eliana Drenkard, looked at the colonies in detail, they found the bacteria weren't actually mutated to be resistant. Instead, the bacteria had shifted into an altered form that made them more resistant to antibiotics.
When the antibiotic medium was removed, the bacteria would shift back to their regular form.
While in their antibiotic-resistant form, the bacteria are more likely to form biofilms -- structured communities of the organisms. However, Ausubel says, "the resistance to antibiotics is not solely a consequence of being in the biofilm
The bacteria themselves are inherently more resistant even before they enter into the biofilm."
The molecular changes that occur in this bacterium are not yet clear, but Ausubel says that in other cases where the shifting has been studied in detail, it usually involves a rearrangement of the bug's DNA.
"There's a mechanism that changes it back to the other position, so it's not really a permanent mutation," says Ausubel, explaining that a protein called PvrR appears to play a regulatory role in the shift.
George O'Toole, an assistant professor of microbiology and immunology at Dartmouth Medical School, says the researchers have revealed the first of three steps involved in how bacteria make the shift to an antibiotic-resistant state. "They have one of the proteins that's involved in controlling the whole process," he says.
A yet-to-be-determined switch follows the activation of this regulatory protein, and the final step is the actions of genes that protect the bacteria from antibiotics.
O'Toole, author of a commentary accompanying the study, says that any of the three steps are potential intervention points for new antimicrobial agents.
"If you can have the regulatory protein either on or off such that it pushes the [bacteria] towards the antibiotic-sensitive state, that's great," says O'Toole. "If you can affect the switch so that the switch can't go to the resistant state, that would be great. And if you actually stop the function of the proteins that protect the [bacteria] against antibiotics, that would work, too."
It may be that this antibiotic-resistant form of P. aeruginosa is the form found in the lungs of people with CF. However, O'Toole stresses this has not yet been confirmed, and that any new therapies based on these findings are still years away.
Still, he says, this study is a step in the right direction towards understanding the high level of antibiotic resistance of biofilms: "It will open up a new area of research that might be very fruitful for developing new treatments."
Ausubel says that his team's future research will involve studying the switch in greater detail, and looking for ways to control it.
What To Do
Find out more about cystic fibrosis from the Cystic Fibrosis Foundation or the National Heart, Lung and Blood Institute.
While somewhat technical, this overview of P. aeruginosa and CF from the European Cystic Fibrosis Society is comprehensive and includes a discussion of biofilms.
