Thanks to new screening tools, and some luck, researchers at the University of Chicago have discovered three unrelated compounds that inhibit the two toxins – edema factor and lethal factor -- that have made anthrax one of the most feared of potential bioterror agents.
In the August 2004 issue of the journal Chemistry and Biology, the researchers report that they used a novel screening technique, developed at the University, to find a small molecule that prevents edema factor from connecting to its target within the cell.
A similar approach, reported in Nature Biotechnology in May, resulted in a compound that inhibits lethal factor, the other anthrax toxin. And a study published in PNAS in February showed that a drug already approved to treat hepatitis was also effective in the lab against edema factor.
"This is dramatic example of how progress in basic science can be applied quickly, effectively and unpredictably to clinical problems," said Wei-Jen Tang, Ph.D., associate professor in the Ben May Institute for Cancer Research at the University of Chicago and an author of all three studies. "Our lab began working with edema factor as a tool to understand basic cellular metabolism, but the knowledge we gained soon led us to three potential therapies."
Because each drug disrupts a different link of the chain of toxic events, the therapies should be complementary. Although all three treatments appear promising in the test tube, none has yet been tested clinically caution the authors. Cell culture and animal testing is underway.
Until 2001, Bacillus anthracis, the bacterium that causes anthrax, was an obscure agricultural pathogen, but that fall someone sent letters stuffed with anthrax spores to several politicians and journalists. Nearly half (5/11) of those infected by breathing in the spores died from the disease. The anthrax mailings triggered a run on antibiotics, but these drugs only work in the early stages of anthrax infection, before the bacteria have had time to spread and secrete toxins.
"These attacks called attention to the need for better therapies for anthrax infection," said Tang.
Fortunately, the Tang lab was already studying edema factor, using it as a molecular probe to understand cell-cell communication. His team had sent a manuscript describing the three-dimensional structure of anthrax edema factor to the journal Nature a few days before the first terrorist use of the microbe became public.
In that paper, Tang and colleagues showed how edema factor did its damage. Inside an infected cell, edema factor connects with a protein called calmodulin. Calmodulin changes the toxin's shape, creating a conformation that functions just like a cellular enzyme called adenylyl cyclase, which helps regulate cell-to-cell signaling.
When edema factor connects with calmodulin, however, it becomes a relentless version of adenylyl cyclase – 1,000-fold more potent -- causing affected cells to become hyperactive. These cells devour their energy stores, lose the ability to regulate their environment, release water, causing edema (swelling) in surrounding tissues, and die.