Photograph courtesy of the EMBL photolab Full size image available through contact |
Tuberculosis is one of the deadliest threats to public health today. An estimated two billion people are infected with Mycobacterium tuberculosis (Mtb), with eight million new cases annually and two million people dying from the infection each year. The situation is further aggravated by the lethal alliance of HIV and Mtb co-infection. HIV patients have weakened immune systems, making them more susceptible to secondary infections and about one-third of HIV patients die from tuberculosis.
The most effective Mtb-specific antibiotics were developed more than thirty years ago, and since that time, the bacterium has learned to defend itself to become resistant to many of the current drugs. The great need for effective drugs has led researchers at the European Molecular Biology Laboratory (EMBL) Hamburg Outstation and a mix of academic and industrial collaborators to study the proteins in the bacterium, which are the functional machines behind the tuberculosis. By studying the structures of these proteins, an approach termed 'structural proteomics', they hope to find more effective drugs against Mtb.
In support of their efforts, the German Federal Ministry of Education and Research has now awarded a 3.5 million Euro grant as part of the government's proteomics initiative "New efficient procedures for functional proteome analysis". The project will be coordinated by EMBL Hamburg and comprises three additional academic partners (Max-Planck Groups for Molecular Structural Biology, Hamburg; Max-Planck-Institute for Infectious Biology, Berlin; Technical University of Munich, Research Center Weihenstefan) and three industrial partners (Biomax, Martinsried; Combinature, Berlin; MarResearch, Norderstedt).
EMBL Hamburg and their partners will work together to apply a step-by-step, structure-based approach to this drug discovery oriented process. In a novel approach, the Max-Planck-Institute for Infectious Biology, Berlin, will analyse the expression of Mtb proteins in infected lung material. Target proteins from Mtb suitable for further analysis will be selected by the scientists from the Technical University of Munich using bioinformatic tools. Their structures will then be solved by X-ray crystallography using the synchrotron radiation beamlines in Hamburg, or by NMR spectroscopy in Berlin. Using the structural data, researchers from the company Combinature and the Research Center for Molecular Pharmacology will test these targets against a high number of potential drug-like compounds to see if any may 'stick' to the target proteins. If the function of these proteins can be blocked, researchers may gain insight into how the bacterium causes disease. Promising targets will be taken through future biological and pharmacological analysis.
Apart from providing more insight into the bacterium's proteins, this project will also enable the partners to develop equipment and infrastructure. A key goal will be to implement a high-throughput crystallization facility at EMBL Hamburg. "This facility will be one-of-a-kind in Europe and will be made available to the academic and industrial research community using high-throughput X-ray crystallography," notes Dr. Matthias Wilmanns, Head of the EMBL Hamburg Outstation. " It will give researchers the infrastructure that is needed to undertake major crystallography projects." In addition, MarResearch GmbH will develop and implement automatic sample changer facilities that automate and speed up the analysis of samples at state-of-the-art synchrotron radiation beamlines. Also, Biomax AG will implement a central database, capable to cope with the large variety of data from the different partners.
"The generous support from the German government will enable our scientists to take great leaps forward in Mycobacterium tuberculosis research," comments Dr. Wilmanns, "We will be able to make significant progress in this battle and be at the forefront of discovering new drugs against this disease."