A team of university scientists has cleared a major scientific hurdle that should lay the foundation for the development of new drugs to combat tuberculosis, a disease that killed 1.8 million people in 2007.
The team uncovered the structure and function of NAD+ synthetase, an enzyme essential for the survival of tuberculosis-causing bacteria, that could help scientists develop drugs to fight the deadly disease.
Assistant Professor of Chemistry and Biochemistry Barbara Gerratana led the study, “Regulation of active site coupling in glutamine-dependent NAD+ synthetase,” which was published on March 8 in Nature Structural & Molecular Biology. Graduate student Melissa Resto and Assistant Professor Nicole LaRonde-LeBlanc also contributed to the study.
“I am hoping that now with the structure and characterization in hand, a drug effective against latent tuberculosis will be developed, thus contributing to the eradication of this disease that still is one of the world’s major killers,” Gerratana wrote in an e-mail.
Gerratana said no current treatments are effective against the latent form of TB, but targeting the NAD+ synthetase enzyme could be key to fighting both active and latent bacteria.
The World Health Organization estimates that one-third of the world’s population are carriers of latent TB, and 10 percent of those people will eventually display symptoms of the disease.
In the past, scientists have had difficulty isolating and blocking the enzyme NAD+. People need NAD+ to survive just as much as the tuberculosis bacteria does, so developing drugs was a tricky process.
By unlocking the inner workings of the synthetase, which creates the NAD+ enzyme, Gerratana anticipates drug development should be easier.
“We have an enzyme essential to tuberculosis which may not be essential in humans, so we may not be burdened so much by the specificity of the inhibitors,” Gerratana said. “The most important aspect of this is we have structure and mechanistic indication that can now be used to design inhibitor molecules to combat the disease.”
TB decline in the United States has slowed in the period of 2000 to 2008 because of emerging drug-resistant strains, according to the Centers for Disease Control and Prevention. The discovery could lead to drugs that kill even resistant forms of the bacteria.
“Our work opens the doors to the structure-based development of drugs targeting this enzyme,” Gerratana wrote.
Gerratana is collaborating with the National Institutes of Health to develop drugs to fight TB. While the findings provide optimism for science’s constant battle against the disease, Gerratana said new drugs would take years to emerge.
“It’s very difficult to say when drugs will be developed at this early stage,” Gerratana said. “Creating drugs is very difficult; this is the first step of a long process. But without this discovery, no structure-based drug development could have occurred.”
LaRonde-LeBlanc said developing a new drug using the knowledge acquired from their research could take 10 to 15 years to hit the market, given the various steps needed to get new drugs approved for use.
Gerratana said she was proud of her team’s work and the impact it could have.
“I’m proud because of what this will mean for TB drug development and proud because our team was able to succeed where others have not,” she said.
jnashdbk@gmail.com
