Balaban reasoned that if she could find a way to block RAP from reaching its target molecule, she could break down the signaling system that allows the release of staph’s devastating toxins. She discovered a chemical she calls RIP (RNAIII inhibiting peptide), which blocks RAP from linking to its target. It is as if an outfielder were standing ready to catch a fly ball heading his way, but he already has a grapefruit in his mitt, preventing the ball from going in. If RAP does not reach its target molecule, the whole communication process breaks down, toxins do not get made, and human immune cells converge on the now-helpless staph germs, ready to mop them up. Balaban claims that RIP can have this effect on free-floating and biofilm-embedded staph alike.
Bacteriologists had it wrong for the past 300 years—bacteria don’t live ?alone. They grow best when each one does its own thing...together.
Some researchers remain unpersuaded by Balaban’s work, however. Richard Novick of the NYU Langone Medical Center, a well-respected staph expert who was also Balaban’s postdoctoral adviser, insists that the TRAP protein does not have any known role in staph biology. In a series of letters to the journal The Scientist, he argues that only one quorum-sensing system has been discovered in Staphylococcus: the agr system. Neither Novick nor any other scientist has been able to reproduce Balaban’s RAP/TRAP experiments in the laboratory. Novick does acknowledge, though, that RIP works. “I don’t question that it has activity. But whatever it’s doing, it’s not inhibiting agr,” he says. “I would guess it could work by interfering with assembly of a biofilm. It should not have any effect on planktonic Staphylococcus. If it did, I would have to revise my view.”
Despite these questions, RIP—which Balaban discovered in Novick’s laboratory—is in the first stages of preclinical testing as a new kind of antibiotic. It costs millions of dollars to develop drugs and get them tested in animals before they can ever be used in clinical trials for safety and efficacy in humans. Fortunately, Balaban has found a naturally occurring chemical equivalent to RIP: hamamelitannin, an extract of witch hazel bark. She has shown that this old-fashioned household remedy, long used by Native Americans, also serves to knock the ball from the outfielder’s mitt. In her tests, hamamelitannin has the same chemical effect as synthetically produced RIP.
In 2003 Balaban’s work caught the attention of Randall Wolcott, a doctor who runs the Southwest Regional Wound Care Center in Lubbock, Texas. Wolcott was developing new antibiofilm treatments, so he contacted the Tufts scientist to discuss both RIP and hamamelitannin. The result: Wolcott broke new ground by adding hamamelitannin to the xylitol and lactoferrin—other natural compounds—he was already using to fight infections. Xylitol is a plant-sugar alcohol that has powerful antibiofilm properties. “I learned about it from a local general practitioner,” Wolcott says. Lactoferrin, a protein found in milk and saliva, kills bacteria by sequestering the iron that they need to function normally.
Since biofilms in chronic wounds are built up by multiple species of bacteria, it is important to attack as many as possible at the same time, Wolcott says. He starts by scrubbing a wound to physically break up the biofilm. Then he hits it with a whole cocktail of antibiofilm agents to attack the colony defenses instead of the bacteria themselves—a departure from usual antibiotic therapy, where one drug, when it fails to resolve the infection, is followed by another, and another. Wolcott’s therapy has had good results. Patients are doing strikingly better with hamamelitannin added to his chemical cocktail than without it.
Typical of Wolcott’s patients is James Porter (not his real name), who, like many late-stage diabetics, suffered for years with chronic wounds on one of his legs. Diabetic wounds typically start as an innocent cut or scratch, and they often go unnoticed because the disease damages nerves so the patient does not feel it. The cut may grow into an ugly, oozing ulcer with areas of yellow, black, or a terrifying green. It consumes more and more tissue until the only recourse is amputation. Several years ago, Porter limped into Wolcott’s medical center. Explaining that he took care of a wife who was completely disabled with multiple sclerosis, he said that he could not manage as an amputee. “Do anything you want, doctor,” he said. “But don’t take my leg.”
Had Porter gone nearly anywhere else, he would most likely have had an amputation, as thousands of Americans do every year. “First we take one leg, then we take the other leg, and then they die,” Wolcott says. “A diabetic amputee has a worse five-year prognosis than anyone with anything except the worst forms of cancer. They die piece by piece, and their suffering is terrible.” Under Wolcott’s care, though, the horrible colors faded from Porter’s foot, and clean pink tissue grew over the wound sites. It took Wolcott’s team nine months to heal the wounds, but Porter walked out of the medical center, leaning on a cane, on his own two legs. Wolcott claims that his methods could save tens of thousands of lives a year nationwide.
In 2006 Wolcott’s work in chronic wound healing, done in collaboration with the Montana State University Center for Biofilm Engineering (once directed by William Costerton), earned the research center a four-year, $2.9 million grant from the National Institutes of Health. Wolcott has found that more than three-quarters of patients with serious diabetic wounds keep their limbs with his treatments. The secret is remembering that bacteria are social, not solitary. “Biofilms are not what we learned in microbiology,” Wolcott says. “To treat them in the short term, we need biocides [xylitol, lactoferrin, antibiotics] in combination. You have to use them at the same time, not sequentially. Quorum-sensing inhibitors are the long-term solution.”
