Breakthrough May Lead to Late-Stage Anthrax Drug

Bijal P. Trivedi
for National Geographic Today

October 24, 2001

Scientists have figured out how anthrax invades the cell and how it
disrupts communication within the immune system eventually leading to
death. The findings were revealed at a press conference yesterday in
Washington, D.C.

The new anthrax findings are examples of
"extraordinary, elegant science," said Anthony Fauci, director of the
National Institute of Allergy and Infectious Diseases. He believes the
new findings may be instrumental in fighting the disease in its advanced
stages; antibiotics such as Cipro are effective only if administered
soon after a person becomes infected.

"You can't rush the science, but when the science points you in the right direction then you can start rushing," says Fauci. Now is the time to translate these findings into something that is useful to public health, he added.

Anthrax research has been thrust into the spotlight since the terrorist attacks of September 11 and even more so since the letters containing a highly toxic form of the bacterium were mailed to journalists and politicians in New York and Washington.

"If you don't kill the anthrax bacterium soon after infection, the microbe has time to produce potentially fatal levels of toxin, against which current drugs are not likely to be effective," said Fauci.

Killing anthrax requires two bullets: one to kill the bacterium and one to block the toxic proteins it produces. As far as killing the bacterium goes antibiotics are effective.

Simply speaking, the anthrax bacterium is a factory that multiplies in the blood stream and continuously pumps out three different toxins. The toxins attack white blood cells—critical defenders against bacterial foes—disarming the body's immune system so that the bacteria may reproduce unhindered.

One of the three toxins produced by anthrax functions like a scout and gatekeeper—it seeks white blood cells and locates a docking port on the cell where it attaches itself. It then creates an entrance for the other two toxins to invade the cell.

But the toxin molecule cannot enter a cell just anywhere. The good news announced Tuesday is that researchers have discovered the specific door, or receptor, that the toxin uses to enter a white blood cell. The receptor, called anthrax toxin receptor (ATR), is the docking site for one part of the toxin.

Once the door is opened the two other toxins enter the cell and essentially sever communication with all other parts of the immune system. Inside the white blood cell, the toxin known as "lethal factor" grabs its target, cutting a critical bond on a single molecule within the cell. The crippled cell is no longer able to communicate with the rest of the immune system.

John Collier of Harvard University in Cambridge, Massachusetts and John Young of the University of Wisconsin in Madison led the work which has been published online by the journal Nature.

In a separate study also published by Nature, Robert Liddington of The Burnham Institute in La Jolla, California, and colleagues have determined the 3-D structure of the "lethal factor" and identified the part responsible for capturing and cutting its target. A drug that blocked this region could render the toxin ineffective.

Based on the research in these two papers, the race to develop drugs has begun.

One potential drug consists of a free-floating receptor "which works as a decoy or sponge to absorb the toxin" before it docks with the real receptor (ATR) on the white blood cells, said the University of Wisconsin's John Young.

The researchers found that when the "decoy" ATR, the anthrax toxin, and rat white blood cells were mixed together in a test tube, the cells were completely protected from destruction.

Another drug developed by Collier and colleagues blocks the toxins from entering the cell. The drug has already been tested in rats and successfully protects the animals against the toxin. Harvard University is currently negotiating with companies to further its development.

However all drugs are at very early stages of development.

"We are ramping up the research to every extent possible, and we are just as emotionally stressed about this as the rest of the public," said Collier.

The major hurdle to drug development is federal funding. "Once the money is in the bank we can contract out some of the work to biotech and pharmaceutical companies," said Collier.

The next stage of research requires "big bucks" and cannot be done in universities. "We will need large quantities of potential drugs and high containment facilities to do animal testing." Collier estimates it will be at least a year or two before a drug is developed for humans.

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