Cutting Edge: Gurdyl Besra

May 4, 2001

With drug-resistant tuberculosis still a danger, the search is on for weak spots in the TB bacterium and ways to attack them.

Tuberculosis has claimed the lives of millions of people in developing countries and is now on the doorstep of Europe. Despite the creation of effective antibiotics to treat the disease in the late 1950s, we enter the new millennium with TB being the leading cause of death from a single infectious agent - more than 3 million people every year. The recent outbreak in Leicester is a reminder of its continuing presence. Meanwhile, drug-resistant strains have established footholds in areas such as the Baltic states and parts of Africa, and many people whose immune systems have been damaged by the HIV/Aids epidemic have been left highly susceptible to TB infection.

In response, efforts are being stepped up to develop treatments for the new strains. At the University of Newcastle upon Tyne, my team of specialists is carrying out intensive research to identify new drug targets - biochemical weak spots found in the TB bacteria but not in humans - as well as drugs that have the potential to disable them.

The bacterium that causes TB, Mycobacterium tuberculosis , is unusual in that it probably survives in human body cells because of the complex waxy envelope that surrounds it. This protective coat is also thought to be one of the main reasons why most common antibacterial agents are ineffective against it. Recently, the Medical Research Council gave our team prestigious "cooperative group" status and the name "TB Magpie". The name has no connection with the nickname of the "Toon" football team, which is based a short distance from our laboratory. In fact, it stands for TuBerculosis: Mycolyl-Arabino-Galactan-Peptidoglycan Initiative and Exploitation, an indication of our proposed strategy to tackle the microbe behind the disease.

Our studies have identified several novel drug targets and new antibacterial agents. We recently found that one of these chemicals, thiolactomycin (TLM), specifically targets a family of enzymes in TB that we believe plays a pivotal role in assembling the microbe's waxy coat. If a drug could interfere with this process, it might rob the bacteria of its protection. The design and synthesis of several TLM derivatives has led us to compounds that are even more potent against TB.

At the same time, parallel studies have found the enzyme that activates the frontline antibiotic ethionamide (ETH), which also attacks the assembly of the bacterium's waxy coat. This is opening new avenues of research relating to both ETH and TLM against the whole family of bacteria related to tuberculosis. It might help improve the efficacy of both agents and even generate new ones.

More recently, we have isolated and purified a key cell wall protein, which belongs to a family of proteins known as the Ag85 complex. This is secreted by the bacterium and helps protect it from attack by the body's defences. In collaboration with colleagues from the United States, we have defined the three-dimensional structure of the protein (published recently in Nature Structural Biology ) and isolated a unique amino acid signature from it, identifying it as a novel drug target.

Working out how the bacteria's waxy coat is assembled and finding the site of action of several major anti-TB drugs, along with the completion of the microbe's genome, heralds a new era in tuberculosis research. Hopefully, it will also lead to new drugs to combat the emerging resistant forms of this terrible disease.

Gurdyl Besra leads the TB Magpie team at Newcastle University with David Minnikin, Michael Barer and Ian Hancock.

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