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Fighting Bacteria With Inside Information
Scientists discover a protein that keeps lethal biofilms from growing
By Kate Dalke

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Biofilms are the squatters of chronic infection. They congregate, slime, and linger on surfaces in the human body—places like hip replacements, contact lenses, catheters and wounds. These drug-resistant communities of bacteria are hard to evict. They live layer upon layer in their own goo.

Biofilms can be deadly. In cystic fibrosis, they clog the lungs of patients—permanently infecting airways and eventually causing death. Biofilms are resistant to even the most aggressive antibiotics.

Five stages of biofilm development in Pseudomonas aeruginosa. View photos

In a recent study, researchers have discovered a protein in human tears, mucus, sweat, and milk that blocks biofilms from growing. The protein lactoferrin discourages bacteria from clumping into biofilms. Lactoferrin stimulates 'twitching,' which causes the bacteria to wander around rather than form harmful clusters.

Pradeep K. Singh, of the University of Iowa College of Medicine in Iowa City, led the study that was published in Nature. He and colleagues hypothesize that lactoferrin's affinity for iron prohibits biofilm growth. Lactoferrin acts as a signal: It tells bacteria that iron is in short supply, an essential nutrient for biofilms. Therefore, the bacteria go elsewhere to build their elaborate homes.

Lactoferrin could provide a sort-of shield against infections, says Singh. Coating inserted medical devices or wounds with the protein could prevent biofilms.

The effects of lactoferrin on P. aeruginosa biofilms after three days. Left image: Without lactoferrin, the cells congregate. Right image: With lactoferrin, the cells wander freely.

Until the late seventies, no one even knew biofilms existed. Scientists thought most of the bacterial world was made up of free-floating bacteria. They developed antibiotics and vaccines using bacteria floating in a test tube. In many cases, the medicines just didn't work—prostatitis, middle ear infections in children and periodontal disease to name a few. As it turns out, scientists were targeting the wrong kind of bacteria.

"We were going after a target that simply wasn't there," says J.W. Costerton, who heads the Center for Biofilm Engineering at Montana State University.

Scientists did not realize that biofilms are bacteria's natural and preferred habitat. Biofilms cannot be seen with the naked eye and their three-dimensional structure was difficult to discern using traditional microscopes.

"It is the equivalent of botanists only studying the seeds of plants, but not the plants themselves," Costerton says. "Free-floating bacteria are a little like seeds and we've studied the heck out of those seeds."

‘Free-floating bacteria are a little like seeds and we've studied the heck out of those seeds.’

The Center for Biofilm Engineering was founded in 1990 and is funded by the National Science Foundation to investigate the emerging field of biofilms through the integration of various disciplines. Biofilms are found not just in the human body, but also throughout the natural and industrial world. They coat the surfaces of rocks in streams and rivers; they colonize in and corrode metal pipes; and they grow inside distribution pipes for drinking water, causing contamination of water supplies. Engineers, biologists, chemists, and environmentalists collaborate at the center to study biofilm systems.

"These are really the early days of biofilm research," says Costerton. Only in recent years have biofilms been studied in a genomic sense. In 2000, the sequencing of Pseudomonas aeruginosa—the bacteria in cystic fibrosis biofilms—has opened up new areas of research.

The genes and proteins involved are clues to what makes biofilms so strong and resistant to antibiotics. Figuring out what proteins are on the surface of cells will make them easier to target.

"Advances in proteomics and genomics are allowing us to move towards investigating more complex systems like biofilms," says Matthew R. Parsek, of Northwestern University in Evanston, Illinois, who collaborated on the study with Singh.

Parsek studies the signals between bacteria within a biofilm. The cells have some sort of language or blueprint to communicate. When enough of them get together, certain genes are activated. Turning on these genes gives bacteria a green light for biofilm growth.

The recipe of a biofilm's slimy matrix is also of interest to Parsek. He uses a combination of genetics and chemistry to study the effects of biofilm secretions.

Scientists are also discovering the radical changes a bacterium goes through to adapt to life in a biofilm. When it's raining outside, you or I will put on a raincoat to adapt to the change in environment. Bacteria adapt to change by activating different genes and proteins depending on their environment.

The changes in these genes and proteins vary so much that the bacteria almost look like different species from one stage to the next, says David G. Davies at Binghamton University, State University of New York. So much change makes it difficult to tailor drugs or therapies to fight infection.

Scanning electron micrographs of a P. aeruginosa biofilm on the surface of a granite pebble.

Davies and his colleague Karin Sauer, also at Binghamton, have undertaken a project to identify the proteins that change throughout the various stages of biofilms. They have identified five stages: reversible attachment, irreversible attachment, stage one maturation, stage two maturation, and dispersion.

The researchers hope to identify 800 proteins whose levels change during the five stages. They are using the genomic work that has already been completed on P. aeruginosa to chip away at the proteomics of the microorganism.

"All of the proteomics research rests on the genome research of P. aeruginosa," says Davies. "Without the sequence, we would never have even conceived of identifying 800 proteins in one summer."

See related GNN article
»The Pseudomonas aeruginosa genome

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Singh, P.K. et al. A component of innate immunity prevents bacterial biofilm development. Nature 417, 552-555 (May 30, 2002).
Whiteley, M. et al. Gene expression in Pseudomonas aeruginosa biofilms. Nature 413 860-864 (October 25, 2001).

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