HMS Researchers Find New Anthrax Treatment

Research performed by scientists at Harvard Medical School (HMS) and Beth Israel Deaconess Medical Center may lead to the production of drugs to combat the deadly toxin secreted by anthrax bacteria.

The drugs could prove a more effective treatment for exposure to anthrax since current antibiotics combat only anthrax bacteria and not the toxins they secrete.

Under normal circumstances, anthrax toxin is activated when an enzyme called a protease binds to one of its components, called anthrax lethal factor.

In a study published in the January 2004 issue of Nature Structural & Molecular Biology, the Harvard researchers identified six molecules that could act as protease inhibitors, attaching themselves to the protease and preventing it from binding with anthrax lethal factor. This, in turn, would block the activation of the toxins.

Anthrax toxins were proven lethal in 2001, after five individuals died as a result of exposure to anthrax spores contained in a series of mailings across the U.S., according to Lewis C. Cantley, senior author of the study and chief of the Division of Signal Transduction at Beth Israel. The deceased victims were successfully rid of anthrax bacteria by antibiotics, thus proving that buildups of anthrax toxin—which would not have been counteracted by the antibiotics—must have been the cause of death.

An estimated 75 percent of inhalation anthrax cases prove fatal, according to the Centers for Disease Control and Prevention. This high mortality rate may result from the deceptive initial symptoms of inhalation anthrax infection, which resemble those of influenza. By the time a correct diagnosis is rendered, the anthrax bacteria may have already released enough toxin to kill a host—rendering antibiotics useless.

The HMS research comes on the heels of a Dec. 2 announcement by Avanir Pharmaceuticals that it is developing an antibiotic that, taken just once before anthrax infection, would both kill anthrax bacteria and prevent anthrax toxin from entering cells.

Avanir’s antibiotic would be more powerful and possibly more effective than the current anthrax vaccines that require booster shots every year to remain potent and that combat only anthrax bacteria. But unlike the Avanir antibiotic, Cantley said he hoped that a drug designed to inhibit anthrax lethal factor would be effectively administrable after contraction of anthrax, thereby lessening the need to inoculate large populations and saving lives in cases of late diagnosis.

“The drug we envision could inhibit the toxin even after the toxin is released into the cell,” Cantley said. “It could be administered successfully in what you might call the late stages of lethality.”

According to Cantley, the next stages of drug development will involve experimentation on mice, which can be performed in an academic setting.

Once those tests prove successful, the private sector will become involved in creating a drug, and Cantley’s research partners at Fort Dietrich military research base in Maryland will take over testing on primates. A drug to combat anthrax toxin cannot be tested on humans because of the ethical and legal dilemmas of exposing humans to a potentially deadly disease.

Cantley said that under normal circumstances, the development of an FDA-approved drug following the identification of key molecules would take approximately 10 years. But the process might be speeded somewhat in this case, he said, because of the U.S. military’s fear that inhalation anthrax, the most devastating form of the disease, might be used in a biological attack against major cities.

Pharmaceutical companies would not ordinarily be interested in pursuing a drug to combat anthrax toxin because of the low likelihood that an average person would be exposed to anthrax, Cantley said. But because of the prospect of obtaining lucrative government contracts, private companies have already expressed interest in creating such a drug, he added.

Private companies may also be encouraged about their chances of developing a successful drug because protease inhibitors have thus far proven the best method to slow the progress of HIV infection, Cantley said.

“Because of drugs to treat AIDS, the idea that you can give humans a designed protease inhibitor that humans can tolerate is encouraging,” he said. “This is especially true with anthrax because an anthrax patient might need treatment for only one or two days and could therefore tolerate greater levels of side effects than could an AIDS patient, who would need to tolerate treatment for years.”

The study also yields hope because the potential protease inhibitors identified have a high degree of what Cantley called “bioavailability,” or effectiveness in reaching target sites. The molecules that stopped the spread of anthrax toxin in the clinical study are between 0.5 and 5 micrometers in size—small enough to be able to permeate a human cell membrane.

The small size of the molecules also signifies an increased likelihood that humans could orally ingest a drug made up of these molecules without suffering acute side effects, said Cantley. Moreover, smaller molecules are generally less costly to synthesize into drugs, Cantley said.

The protease inhibitors identified by the study were discovered by utilizing technology developed in 2001 by Cantley and Benjamin E. Turk, another Beth Israel scientist and an HMS research fellow in medicine.

The technology, called a “mixture-based peptide library,” enables the screening of billions of peptides to narrow the field of potential protease inhibitors.

Cantley said that because there was little known about anthrax at the time that this technology was developed, his team focused on finding potential inhibitors of anthrax lethal factor.

Although Cantley said that he was aware of the potential for the use of anthrax as a biological weapon when he began the study, he acknowledged that the Sept. 11 terrorist attacks increased the immediate importance of his research.

“We were working on this study in the spring of 2001 and had made quite a bit of progress,” he said. “We got the grant to continue to fund our work just at the time that the letters [containing anthrax] hit.”

—Staff writer Alan J. Tabak can be reached at tabak@fas.harvard.edu.