New active compound for tuberculosis enters clinical trail

Scientists from two research consortia and companies are joining forces

The first antibiotic against tuberculosis developed in Germany is now entering clinical trials. The newly developed test substance, BTZ043, is also effective against multi-resistant pathogens that are making treatment increasingly difficult worldwide. The project is led by scientists from the Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute - (Leibniz-HKI) in Jena and the Ludwig-Maximilians-Universität (LMU) Munich. The InfectControl 2020 consortium and the German Centre for Infection Research (DZIF) support the studies substantially.

In recent decades, the problem of antimicrobial resistance has dramatically worsened worldwide. Today we are facing a situation where there are more and more resistant bacteria strains against which only a few antibiotics still help. For tuberculosis, the situation is particularly difficult as several antibiotics must be administered simultaneously for the treatment to work. In addition, tuberculosis pathogens are increasingly resistant to these antibiotics. In order to develop new forms of therapy, several new active compounds are urgently needed, ideally with different mechanisms of action.

Active ingredient targets a new site on the pathogen

BTZ043 belongs to a new class of antibiotics, the benzothiazinones. BTZ043 was the first member of this family of substances to obtain worldwide patent protection for its effect against the tuberculosis pathogen. "The active substance irreversibly binds to an enzyme that mycobacteria - the pathogens of tuberculosis - need to build up the bacterial cell wall," explains Dr. Florian Kloß, head of the Transfer Group Anti-infectives at Leibniz-HKI, which is funded by InfectControl 2020. "This enzyme can no longer function, holes are formed in the cell walls of mycobacteria and they leak," adds DZIF scientist Prof. Michael Hoelscher, Director of the Tropical Institute of the LMU in Munich. This attack on the tuberculosis pathogens is so specifically targeted that BTZ043 only fights these pathogens, but not other bacteria that might be important for the human organism.

Clinical trial tests safety and efficacy

After approval by the Federal Institute for Drugs and Medical Devices (BfArM) and the Ethics Commission of the Bavarian Medical Association, the volunteers for the clinical trials of BTZ043 can now be recruited. Under the direction of Prof. Hoelscher, up to 40 participants will receive the antibiotic at the Nuvisan study centre in Neu-Ulm. "We want to make sure that the drug is well absorbed and well tolerated in the body. For this purpose, a very small dose is administered once, which is then increased step by step in the next test subjects," Hoelscher explains the procedure. The aim of the study is to achieve the dosage that has shown good efficacy in animal models. This effective dose is well below the maximum amount tested on animals and is still well tolerated.

Together against infections

A team of scientists and entrepreneurs is involved in the development of the new tuberculosis drug. The active substance BTZ043 was discovered at the Leibniz-HKI in Jena. Since 2014, the Leibniz-HKI and the Hospital of the LMU Munich have been cooperating in the InfectControl 2020 consortium and the DZIF to further develop the drug. The Leibniz-HKI is responsible for the development of analytical detection methods and the precise investigation of uptake, distribution, metabolism and excretion in animal experiments and in humans. As a sponsor, the LMU Hospital is responsible for the preclinical and clinical development as well as the quality and safety of the drug. The highly effective substance is manufactured by a medium-sized pharmaceutical company, Hapila GmbH in Gera. In addition, the company develops the manufacturing process in accordance with all relevant pharmaceutical legislation and internationally applicable regulations and is supported for this purpose by the Free State of Thuringia. The cost of drug development amounts to several million euros and is only possible through joint financing from the public and private sectors: in particular the two research alliances InfectControl 2020 and DZIF are involved in this drug development. Both are programs initiated by the Federal Ministry of Education and Research to promote antibiotics and infection research in Germany.

Prof. Axel Brakhage, Director of the Leibniz-HKI and Professor at the Friedrich Schiller University Jena, has accompanied the development of the drug since its discovery: "It requires immense financial and organisational efforts when publicly financed institutions get involved in drug development. The threatening spread of multi-resistant pathogens, however, makes it absolutely necessary to create progress in this sector and to reach out to industry for which this is a less lucrative source of income. Thanks to the transfer group funded by InfectControl 2020 and our partners from DZIF at the University Hospital of Munich, we have already gained a lot of experience that we can also apply to future development projects," said Brakhage.