New Possible Drug Targets Emerge for Drug-Resistant Tuberculosis

Professor Stephen Seah and Stephanie Gilbert (photo by K. White)

Tuberculosis remains one of the top causes of death worldwide today, but researchers in the Department of Molecular and Cellular Biology have identified a new potential drug target that might help fight this long time health scourge.

While investigating cholesterol metabolism in Mycobacterium tuberculosis, the bacterium that causes tuberculosis, Prof. Stephen Seah and graduate student Stephanie Gilbert identified an enzyme crucial to the process that could someday serve as a target for new treatment strategies.

 “In the ‘70s, researchers were initially interested in studying these enzymes in order to more efficiently produce steroid drugs,” says Seah. “Interest waned for a while, but has renewed with the discovery that cholesterol metabolism by M. tuberculosis is important for its survival in the human host.”

With multidrug-resistant strains of M. tuberculosis on the rise, there is a growing need to find new ways to stop the bacteria. One approach is to disrupt metabolic processes that are essential to the survival of the bacteria.  Seah and Gilbert’s study of cholesterol breakdown in M. tuberculosis – a process that provides energy which is critical to the bacteria’s survival – revealed an important role for a major aldolase enzyme called Ltp2 that is involved in breaking the side chain of cholesterol.

Interestingly, the duo also discovered that Ltp2 interacts with another cholesterol-degrading enzyme, called a hydratase.  This interaction increased the efficiency of both enzymes.  In the absence of Ltp2, the hydratase can only degrade 30% of the usual amount of cholesterol - but when Ltp2 is present, complete transformation of the steroid occurred.  When Ltp2 interacts with a particular portion of the hydratase, called the DUF35 domain, its aldolase activity also increases.  

Overall, the study shows that Ltp2 is pivotal to M. tuberculosis ability to catabolize cholesterol, and interfering with its function could someday help combat multidrug-resistant strains.

Seah’s lab is now investigating why the DUF35 domain of the hydratase initiates Ltp2 activity by examining the shape of these proteins.

“We have already started looking at the structure of an enzyme from another bacterial species with highly similar structure and function to Ltp2,” says Seah. “This can give us an idea of its function and why it requires association with DUF35 domain.”

The study is an exciting example of how delving into bacterial protein structure and function can assist in the discovery of new treatments for disease by identifying new targets for treatment, giving us the upper hand in the arms race against drug-resistant bacteria.

Undergraduate student LaChae Hood also contributed to the study.  This project was funded by the Natural Science and Engineering Research Council of Canada.

Read the full study in the Journal of Bacteriology.

Read about other CBS Research Highlights.