Ever so often there will be another news report about an anthrax scare at a post office or on Capitol Hill in Washington, D.C., giving everyone a reminder of the way the world has changed since Sept. 11, 2001.

UAB researchers Wayne and Christie Brouillette are trying to develop drugs to combat anthrax, plague and tularemia — three pathogens for which there are no drugs currently available to treat.

The majority of these incidents have come to pass without injury, and the substances in question have been identified as baking powder or another non-toxic material. But the U.S. government sees the threat of anthrax, plague and other engineered, multidrug-resistant strains of bacterial pathogens as real. And in its estimation, that means that new antibacterial drugs that act on these types of targets are needed for protection.

UAB researchers Christie and Wayne Brouillette, Ph.D., are trying to develop drugs to combat anthrax, plague and tularemia. No drugs specifically designed to combat the three pathogens are available on the market, let alone a single drug to hit all three. But the Brouillettes say they are making progress in developing drugs they hope can one day be administered to anyone exposed in a real bioterrorist event – and save their life.

“Some time ago, the Center for Biophysical Sciences and Engineering received funding from the Defense Advanced Research Projects Agency (DARPA) to discover new targets for high-risk pathogens that might be an interest for bioterrorism,” says Christie Brouillette. “Wayne and I were involved in the development of one of those targets, and with our own funding we’ve made pretty good progress in discovering effective compounds.”

Dangerous substance
Anthrax, plague and tularemia are categorized by the U.S. government as Class A pathogen agents, the most dangerous class of virulent pathogens. Anthrax itself actually is a naturally occurring spore, found all around in nature, but it is normally dormant and its low concentrations rarely pose a natural risk to humans.

“You can find anthrax in the dirt, there’s just not enough of it to be harmful,” says Wayne Brouillette.

“Also, it has to be put in a nutritive environment before it becomes dangerous.” Adds Christie Brouillette, “In its spore form it’s actually easy to handle. It’s easily dispersed, too, which is why it’s a good bioterrorism agent.”

Because these agents pose such a significant risk, there is a greater need for many approaches for protection and treatment, especially given the threat of multi-drug-resistant strains. The Brouillettes say a number of viable, alternative drug therapies are needed in addition to vaccines.

Rapid treatment
Treatment of patients suspected of exposure to a Class A pathogen must be simple and rapid, says Christie Brouillette.

Early symptoms for anthrax, plague and tularemia essentially are the same, making a definitive diagnosis impossible without pathogen-specific tests. But mortality is extremely high and rapid after the onset of symptoms from inhaled anthrax or pneumonic plague.

“If someone is sick, you may not have time to wait for the outcome of a test,” Christie Brouillette says. “The right choice for post-exposure treatment could be made much easier if a single drug was known to be efficacious against all of the diseases.”

Because of the real threat of engineered multidrug-resistant strains of anthrax, plague or tularemia, new antibacterial drugs that remain effective are needed. One way to achieve this is to find new drugs that act on novel drug targets.

The Brouillettes and their team have achieved preliminary successes for compounds they have already identified to combat one of the enzyme targets found in Bacillus anthracis. These compounds appear to have broader applications because they also prevent the growth of common multi-drug-resistant bacteria. Their goal is to get drugs ready for late pre-clinical trials and “establish they not only are safe, but that they prevent or cure the disease in animal models,” Christie Brouillette says.

Marriage an advantage
The Brouillettes have been married for more than 30 years and have been working at UAB since 1979. Ironically, this is the first time the pair has worked together on a work-related project.

Wayne Brouillette’s work is in the fourth of a five-year, $1.5 million grant from the NIH. Christie Brouillette has begun the first year of a $5.3 million grant. There is distinctively different work going on with both grants, but the topical overlap was deliberate so that the results from Wayne’s grant (Christi is co-PI) could naturally feed into Christie’s (Wayne is co-PI).

“Prior to this project, there was never an overlap of interest, and so the question of whether we should work together or not wasn’t an issue,” Christie Brouillette says. “This project just kind of evolved, and we’ve found our skills are highly complementary in a drug-discovery and development environment.”

This means sometimes their work does go home with them, but Wayne Brouillette actually sees that as an advantage.

“I think the NIH is getting their money’s worth because we’re talking about compounds while we’re brushing our teeth,” he says.