New angle in cause of tuberculosis discovered - scientists hopeful for new therapy

By Dr. Ananya Mandal, MDApr 26 2011

In a new study published Monday, researchers from the US have isolated the enzyme that allows tuberculosis (TB) to destroy lung tissue. This discovery could speed the search for treatments.

Tuberculosis is a highly contagious and often fatal disease that kills two million people worldwide each year. Tuberculosis is caused by a bacterium, Mycobacterium tuberculosis, which gets into the lungs and causes coughing. That spreads the bacteria in the air where it can infiltrate other people's lungs. The only treatments available are lengthy antibiotic regimens, which may not work against drug-resistant strains.

The disease has been around for thousands of years but scientists are only now learning how it works. This study notes how this enzyme drives the destruction of lung tissue is called MMP-1, and enzyme-inhibitors are already available which could be used to treat it, said the study in the Journal of Clinical Investigation.

Study co-author Paul Elkington from Imperial College London said, “Standard TB treatment has remained unchanged for 35 years, and no current treatments prevent the lung destruction that TB causes… These findings suggest that drugs available now might be able to reduce deaths from TB.” This study shows that there may be a new avenue for therapy.

For this study the team treated human cells infected with TB -- which were associated with a boost in the enzyme MMP-1 in the lungs -- in the lab with an MMP inhibitor that has been proven safe for humans in clinical trials to treat arthritis. “We demonstrate that Ro32-3555, a compound that has been used in phase III clinical trials for arthritis, can suppress M. tuberculosis-driven MMP-1 activity,” said the study. “Therefore we believe it represents a novel therapeutic target to limit immunopathology.” Drugs that act by inhibiting MMP enzymes were widely developed in the 1990s as some showed early promise against cancer. The researchers said more studies are needed to demonstrate whether MMP inhibitors can prevent lung damage from TB on a larger scale.

“Standard TB treatment has remained unchanged for 35 years and no current treatments prevent the lung destruction that TB causes,” said Paul Elkington from the Infectious Diseases and Immunity department at Imperial College London (ICL), who led the study. “These findings suggest that drugs available now might be able to reduce deaths from TB.” “Until now, we haven't had a convincing explanation of how lung destruction is caused by TB,” said ICL's Jon Friedland, who also worked on the study. “We hypothesized that protease enzymes must be involved, since nothing else could break down the strong collagen fibers that make up the scaffold of the lung. The results of this study provide strong evidence to support that idea.”

Elkington said his team now hoped to collaborate with drug companies to see if MMP inhibitors can prevent lung destruction in TB patients. He said he had contacted the Swiss drugmaker Roche about a possible collaboration and was awaiting a reply. He said that “with a fair wind,” clinical trials using RO323555 in TB patients could start in about a year's time.