Antitubercular Agents
Benzothiazinones, Pyridomycin and analogues
By 1900, in Northern Europe almost every twenty year old man carried Mycobacterium tuberculosis, even though most never developed the disease. Bad times for the host such as of illnesses, cold weather, or malnutrition were good times for the guest, the opportunistic Mycobacteria. During the 1970s, tuberculosis hospitals in Europe were gradually closed, and the term 'consumption' for tuberculosis was forgotten. At the beginning of the 21st century, international efforts to get TB under control again have to be intensified. Three of the wealthiest countries of the world, the 'G8', highlighted tuberculosis, AIDS and malaria as "the" three pandemics and put a lot of money in diagnosis, prevention and therapy. The European Commission (Directorate General for Health) the Bill and Melinda Gates Foundation and others specifically fund tuberculosis research – the mycobacteria are returning. Actually, they were always there: dormant (persistent) in healthy people, fulminant and dominant in tuberculosis patients. In 2011, the 'WHO Global TB Control Report' reported that for the first time the number of tuberculosis patients had declined, albeit at a high level: 8.8 million in 2010 compared to 9.0 million in 2005, casualties 1.4 million in 2010 compared to 1.8 million in 2003. This was mainly due to consistent, local donation based treatment programs in poor countries. The reduced mortality rate was largely due to improved disease control in the P.R. China. However, it is estimated that worldwide one third of TB disease cases are not identified diagnostically and statistically. This would leave about 4 million people without a therapy.
Despite the existence of WHO’s World TB Day on March 24, TB is a disease that is still underrepresented in the mass media in relation to the harm it causes worldwide. In Europe, an alarming number of MDR (multi-resistent) mycobacteria occur in places like London, a meeting place for all peoples and global developments.
With intesified research efforts, hopefully a few new anti-tuberculosis drugs will be introduced in the following years. Recently, bedaquilin was approved. The benzothiazinones (BTZs), discovered in the Hans Knöll Institut (Jena), are among the strongest poisons against mycobacteria (MIC in the pg/ml range) and are presently being developed further.
BTZs actually constitute one of our research projects in this field. Because there are few BTZ derivatives, we design and synthesise derivatives that are characterised by easier synthetic accessibility and stability. Activity tests are performed in the Hans Knöll Institut (Jena). We have been able to find derivatives that inhibit the growth of mycobacteria at concentrations below 1 nmol/L.
A second project focuses on a natural depsipeptide, pyridomycin, which was identified as a potent anti-tuberculosis drug some time ago. So far, the compound has been examined due to its very poor accessibility. It was recently shown to directly inhibit the molecular target of isoniazid, the most important antitubercular drug. We work on the synthesis of pyridomycin and analogues.
Cooperation:
Dr. Ute Möllmann and Dr. Michael Ramm, Leibniz Institute for Natural Product Research and Infection Biology (Hans Knöll Institut), Jena.
Dr. Lluís Ballell, GlaxoSmithKline, Diseases of the Developing World, Madrid, Spain.
Dr. Chun-wa Chung, GlaxoSmithKline Medicines Research Centre, Stevenage, UK.
Dr. Argyrides Argyrou, GlaxoSmithKline Medicines Research Centre, Stevenage, UK.
Prof. Dr. Yossef Av-Gay, Infection and Immunity Research Centre, University of British Columbia, Vancouver, Canada.
Prof. Dr. Shuangjun Lin, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, P.R. China.
PhD and Diploma Theses:
A. Richter, Diploma Thesis (Pharmacy), Halle 2013.
A. Eichner, Diploma Thesis (Pharmacy) München and Halle 2013.
I. Rudolph, PhD Thesis 2014.
K. Laqua, PhD Thesis in progress.
M. Klemm, PhD Thesis in progress.
A. Richter, PhD Thesis, Halle 2017.
H. Asfaw, PhD Thesis, Halle 2017