Tackling antibiotic-resistant bacteria
When he was studying for his doctorate in microbiology, Mark E. Shirtliff thought he knew a lot about bacteria.Then things got scary.He discovered that bacteria can band together into sheets – called biofilms. When they do, they alter their behavior. They build complex communities, establish lines of communication and coordinate their actions. Like ants, the microbes find power in numbers. And they’re nasty.”Infections that should respond to antibiotics don’t,” Shirtliff said. “They become 50 to 500 times more resistant.”With drugs often useless against biofilms in the human body, Shirtliff is trying to turn the tables on the slippery infections.The assistant professor at the University of Maryland Dental School received $1.25 million this month from the National Institutes of Health for research into vaccines that might prevent the deadly films from forming in the first place.Although the public rarely hears it in popular discussions of health issues, the term “biofilm” was coined in a 1978 Scientific American article by William Costerton, now of the University of Southern California Dental School. He used it to describe microbes that clump together on wet surfaces.”It came up in dentistry first,” Costerton said. “They called it plaque. I just proposed (that) the biofilm isn’t just in the mouth, but everywhere.”In fact, biofilms are just about everywhere. They coat everything from Alpine river rocks to neglected teeth. Every year they cause billions of dollars of damage to ship hulls, oil pipelines and machinery by corroding metal surfaces and clogging up the works.These plaques often contain a variety of microorganisms, including bacteria, protozoa and algae suspended in slimy glue called polysaccharide that holds them together and binds them to surfaces. When enough of the organisms have collected, they undergo metabolic changes that make them better team players.”We tend to think of them as primitive single-celled organisms,” said Phil Stewart, the director of the Center for Biofilm Engineering at Montana State University. “But there is a lot of cooperation and coordination comparable to something more like an ant colony. It allows them to accomplish more than they could on their own.”Particularly vexing is the ability of virulent bacterial infections to resist attack after forming a biofilm. “We could pump bleach into your system,” Shirtliff said, “and it probably wouldn’t do anything.”That’s saying something. Chlorine bleach is the microbiologist’s ultimate weapon – it’s used to disinfect the labs that house the world’s most dangerous germs.Like soldiers hiding in a castle, the bacteria inside the film are protected from drugs designed to kill them. The cells are also starved for nutrients. This makes them grow and divide slowly – providing even more drug resistance, since antibiotics often target fast-growing cells.The stress also puts biofilm bacteria on the defensive, causing them to release caustic acids and proteins. “They start freaking out,” Shirtliff said. “They turn on stress response genes that make them attack the antibiotic.”Compounding the problem, the stress response tricks the natural immune system into using the wrong attack plan. When themacrophages and other white blood cells that form the body’s police force arrive on the scene, they’re ambushed and destroyed by the biofilm’s arsenal of proteins and acids.Biofilm infections often return because antibiotics kill only the free-floating – or planktonic – bacteria. When a patient stops taking the drug, new free-roaming bacteria emerge from the biofilm and the infection spreads again.Scientists estimate that 65 percent to 80 percent of chronic infections in industrialized nations linger on because of biofilm formation. Biofilms appear in patients with cystic fibrosis, gum disease and chronic inner ear, urinary tract and bone infections.Medical devices such dental implants, catheters, artificial joints and heart valves are vulnerable to biofilm formation.In his research, Shirtliff has focused on one particularly bad actor that has received plenty of press lately: methicillin-resistant staphylococcus aureus (MRSA). The antibiotic-resistant bacteria kill about 90,000 people in the United States every year, according to the CDC.Because MRSA infections are difficult or impossible to eradicate once a biofilm is fully formed, Shirtliff is searching for a way to prevent the films from growing.The trick, he believes, is to hone in on the odd behavior of the biofilm bacteria. He has identified proteins the bacteria produce in abundance as they form a film and hopes to develop antibodies that will target those proteins.Like an army attacking a half-built fortress, the antibodies would attack the immature biofilm and destroy it before its defenses are fully formed.”The antibodies come in and deactivate the proteins and can destroy the biofilm,” he said. “The immune cells could also come in safely then and attack as well.”To test his theories, Shirtliff grows MRSA biofilms in silicon tubing in his lab at the dental school and looks for protein targets.Anti-biofilm vaccines he has developed have proven effective for treating rabbits with MRSA bone infections. He hopes to move on to clinical trials in humans within four years, he said.He said a vaccine might be the best way to combat MRSA because the bacteria are so widespread. “Here in the United States,” he said, “it’s hard to cork that bottle.”
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