Tuberculosis inhibitors brought closer by new target sites

Tuberculosis bacteria need to break down cholesterol in order to survive in the lungs, microbiologist Maarten Wilbrink has discovered. He was awarded a PhD by the University of Groningen on 11 March 2011. As soon as cholesterol breakdown is shut down, the immune system recognizes and destroys the tuberculosis bacteria that have managed to infiltrate the lungs. This discovery means that the search is now on for drugs that block the breakdown of cholesterol.

Together with colleagues from the universities of British Columbia and Oxford, Maarten Wilbrink investigated cholesterol breakdown in Rhodococcus jostii, a soil bacterium. Using microarray techniques, he identified the genes involved in this enzymatic breakdown process. Enzymes that can break down cholesterol are of commercial interest as they can be used to turn vegetable waste into high-grade pharmaceutical compounds.

Wilbrink discovered that Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), uses the same cholesterol breakdown pathway – one that turns out to play an instrumental role in the infection process.

Tuberculosis

Along with AIDS and malaria, tuberculosis is one of the most serious infectious diseases in the world. One third of the world’s population is infected with M. tuberculosis. Every year the disease kills two million people and more than nine million become infected. The number of infections still appears to be rising and more and more M. tuberculosis strains have developed resistance to the available drugs, which further hampers treatment.

Disappearing act

In normal circumstances the human immune system is capable of dealing with infectious bacteria: macrophages engulf invaders immediately and then destroy them. The tuberculosis bacterium, however, is capable of surviving in a macrophage for years on end. ‘Tuberculosis bacteria know how to make themselves invisible to macrophages in lung tissue’, Wilbrink explains. ‘This means they are able to escape detection by our immune system. Cholesterol breakdown appears to play a crucial role in this disappearing act. As soon as the cholesterol breakdown pathway in the TB bacterium is blocked, macrophages are suddenly able to recognize the bacillus again.’

Signal pathways

Just why cholesterol breakdown is essential for the TB bacterium’s survival in macrophages is not yet clear, Wilbrink says. It seems likely that the TB bacteria are in a dormant state, either surviving by using cholesterol from the host’s cell membranes as energy source, or by coating themselves in a protective layer of cholesterol. Wilbrink thinks that there may be another possibility, where the tuberculosis bacterium actively fool the macrophages: ‘Perhaps they use cholesterol to make substances, such as vitamin D, that influence important signal pathways in the macrophage.’

Tuberculosis inhibitors

Charting the cholesterol breakdown pathway in TB bacteria will enable the focused development possible of growth-inhibiting substances. The tuberculosis bacilli would then once again become visible to the immune system. ‘The enzymes in the breakdown pathway are highly suited to use as target sites for drugs’, according to Wilbrink’s supervisor, professor of microbiology Lubbert Dijkhuizen. ‘They’re bacterial enzymes which aren’t present in the human body.’    

Patent application

Dijkhuizen already has a number of ideas for such inhibitors. The University of Groningen took over the patent application for such tuberculosis inhibitors this month from former research partner Organon (now MSD). Dijkhuizen is pleased by this: ‘We want to continue quickly with the search for these inhibitors. Such a promising patent shouldn’t go uninvestigated for too long.’ However, there is still a long way to go, he emphasizes. ‘Developing drugs is a lengthy process; getting a suitable inhibitor on the market will take at least fifteen years.’

Curriculum Vitae

Maarten H. Wilbrink (Sappemeer, 1980) studied molecular biology at the University of Groningen. He conducted his PhD research in the Microbial Physiology research group of the Groningen Biomolecular Sciences and Biotechnology Institute (GBB). The study was funded in part by the NWO’s Integration of Biocatalysis and Organic Synthesis (IBOS) programme. Wilbrink received his PhD from the Faculty Mathematics and Natural Sciences and was supervised by Prof. L. Dijkhuizen and Dr R. van der Geize. His thesis is entitled Microbial sterol side chain degradation in Actinobacteria.

Note for the press

More information: Dr Maarten Wilbrink, e-mail: m.h.wilbrink rug.nl, tel +31 (0)50 363 2257, Dr R. van der Geize, Prof. Lubbert Dijkhuizen

Part of Wilbrink’s research was published in 2007 in the journal Proceedings of the National Academy of Sciences (PNAS). The article (‘A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages’) can be found at: www.pnas.org/cgi/doi/10.1073/pnas.0605728104.