Modern approaches to an ancient disease (2010)

Tuberculosis (TB) is one of the oldest known human diseases and is again becoming a major concern. 

The bacterium responsible, Mycobacterium tuberculosis, is developing resistance to current antibiotics, especially in the “persistent” form of the disease, and treatment regimens are lengthy and difficult to follow. As a result of the HIV epidemic millions of people are also becoming more susceptible to infection. 

Despite a major international research effort, only a few new drugs for persistent TB have entered clinical development in the last 40 years. 

The first of these, PA-824, is currently in phase II clinical trials under the stewardship of the non-profit Global Alliance for TB Drug Development (TB Alliance) in New York. 

Scientists from the Auckland Cancer Society Research Centre, who are members of the Maurice Wilkins Centre, have worked with the TB Alliance to learn more about the biological activity of PA-824 and design improved “second generation” analogues of the drug. 

In the course of their research, they have also come up with a new method for synthesising the drugs, which will simplify and reduce the cost of production. 

In 2010 Associate Professor Brian Palmer and Professor Bill Denny, who led the collaboration with the TB Alliance and University of Chicago, completed a contract to deliver a second-generation drug candidate to the Alliance. 

Their work involved designing and synthesising nearly a thousand second-generation compounds, refining them based on laboratory tests, and selecting the most promising candidates for further development. The final three candidates are now being evaluated by their international collaborators. 

Also in 2010, Maurice Wilkins Centre PhD student Mridula Dogra and colleagues published research that improves understanding of how PA-824 behaves in the body. 

Given to patients as an inactive “prodrug”, PA-824 converts to an active antibiotic when it encounters a particular M. tuberculosis enzyme. 

Mridula’s research confirmed that PA- 824 was selectively activated by M. tuberculosis, and not by a closely related bacterium or normal human enzymes. This provides reassurance that it is unlikely to be activated in tissues unaffected by TB. 

“New Zealand can be very proud that its scientists feature so prominently in the work of the TB Alliance alongside colleagues from some of the world’s top medical research institutes,” says Maurice Wilkins Centre Director, Professor Rod Dunbar. 

“Their achievements are an indication of the strength of drug discovery in this country and its global reach.” 

The research group is now working with the Alliance on an improved “second-generation” analogue of another new TB drug, TMC207, which is currently in clinical trials.

See www.tballiance.org/new/portfolio.php

Image: Micrograph of Mycobacterium tuberculosis. Image courtesy of Dr Ray Butler and Janice Carr (Centres for Disease Control).