Novel targets for short-course tuberculosis therapy
Mycobacterium tuberculosis (Mtb) is the world's leading cause of death from a single infectious agent. Tuberculosis (TB) is epidemic with currently approximately 1.8 billion infected people. The complete eradication of Mtb from an infected patient is difficult largely due to the slow growth rates of this organism and its remarkable ability to persist in a so-called dormant state. This requires antibiotic treatment for several months, which is frequently not strictly followed resulting in incomplete sterilization and recurrent disease. The inevitable consequence of inadequate therapy is the emergence of highly resistant strains, which cannot be treated with the front-line antibiotics for Mtb.
Because of the severe drawbacks of the existing therapies, there is a continuous interest in the discovery of novel compounds against Mycobacteria which allow to shorten treatment duration, have less side effects and lower the risk of resistance development.
We aim at the discovery of new chemical compounds against mycobacteria by establishing new screening assays and using different sources of chemical compounds. For safety reasons we use Mycobacterium bovis (BCG) and Mycobacterium smegmatis as test organisms. In our screening assays we simulate environmental conditions to which Mtb is exposed in the persistent latent state. This state is also called the dormant state, as the bacteria do not grow but maintain their viability. Thus, we do not only detect inhibition of growth by exposure to chemicals, as usually done in drug-screening campaigns, but we also monitor viability of the microorganisms without the need for proliferation. These screening assays were already applied to extracts from myxobacteria supplied by our partners from the Chemical Biology Department. In collaboration with our partners from the AG “Microbial Agents” extracts, which showed biological activity, were produced in larger quantities and the active compounds were purified and chemically identified. With this approach we could discover first new myxobacterial metabolites with activity against M. smegmatis and M. bovis. Currently we investigate in detail their spectrum of activity and the mechanism of action on a molecular basis.
The project was largely funded by the BMBF.