New Substances for Treatment of Tuberculosis
At the DZIF, scientists from Munich, Saarbrücken, Cologne and Borstel have set themselves a joint goal: to discover new drugs for tuberculosis (TB) and/or use available drugs more efficiently in new treatment concepts.
At the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) in Saarbrücken, natural substances from myxobacteria are prepared in a way that they can be used in in vitro-testing systems at the Cologne and Borstel Partner Sites. Here they are tested for their efficacy against mycobacteria, the tuberculosis pathogen. Additionally, these substances are tested for potential toxicity in human cells. Promising non-toxic samples with high efficacy against the TB pathogen are isolated from natural compound mixtures, their structures determined and subsequently further analysed in biological testing systems.
Biological Testing Systems for Drug Research
At the University of Cologne, a testing station was developed in which thousands of substances can be tested for growth inhibiting properties against mycobacteria via several high-throughput procedures. Alongside this, adjunct agents that can be used alongside standard antibiotics are also being tested. Chemists are currently testing numerous substances both in Germany and abroad.
A mouse model was developed at the Research Center Borstel, for improved simulation of the tuberculosis disease. Here, substances selected by the above-mentioned procedures undergo efficacy testing in infected animals. This model is also used to identify agents that do not demonstrate any resistance. Together with partners from the University of Bayreuth, scientists are working on imaging techniques which would enable a more precise determination of the distribution of antibiotics within the tissues and consequently allow for improved dose specifications. Following various verifications, this particular mouse model replaced previous less reliable preclinical models. Newly discovered substances as well as existing new agents (BTZ043, Q203, GSK´147, dedaquiline and delamanid) are to be tested both individually and in combination. Effective agents will subsequently undergo clinical testing.
With these preclinical approaches, scientists intend to accelerate the discovery of new drugs for humans and improve dose specifications. With this approach, higher risk candidates or cases that are not particularly promising, could be identified early on and costly clinical development stopped in time.
From Mice to Humans
The International Trials Unit at the Ludwig-Maximilian-Universität München coordinates large international clinical TB studies (phases I-III). Here, new combination therapies with standard antibiotics are being investigated with the aim of obtaining more effective treatment strategies. Furthermore, a clinical trial is currently being conducted in which the first antibiotic developed in Germany, termed BTZ043, is being tested. The aim is to conduct a first clinical trial in which healthy volunteers are administered a dose that demonstrated good efficacy in animal models. Further trials evaluating new diagnostic methods are being conducted jointly with African partners in international networks such as: CANTAM, PANACEA and TB Sequel.