New therapeutic approach enables more efficient treatment of tuberculosis
Tuberculosis infections can quickly become life-threatening and treatment is often made more difficult due to the resistance of the pathogen. New therapeutic approaches are therefore required that enable efficient treatment even in the case of existing resistances. Scientists from the Technical University of Munich (TUM), Harvard University and Texas A&M University have now identified an active ingredient that, in combination with antibiotics, leads to a significant improvement in therapy.
The researchers "found a substance that interferes with the structure of the bacterial cell membrane" and "even in low concentrations and in combination with an already known antibiotic increases the effect by a factor of 100," according to the TMU. In the treatment of life-threatening tuberculosis infections, the growing number of antibiotic resistances is one of the greatest challenges, and the dense mycomembrane of the pathogens also complicates therapy, since the membrane reduces the effect of many pharmaceuticals.
Mycomembrane protects the pathogen
"The mycomembrane is a lipid bilayer that envelops the cell wall and forms an outer barrier," the experts explain. In his current study, the research team led by Professor Stephan A. Sieber from TUM was able to identify a substance that sensitively disrupts the structure of this membrane of the mycobacterium tuberculosis pathogen. To do this, they looked for a substance with a similar structure to mycolic acids, which form an essential structural component of the mycomembrane. The researchers have published their results in the journal "Angewandte Chemie".
Biosynthesis of the mycomembrane inhibited
Mycolic acids are branched β-hydroxy fatty acids with two long hydrocarbon chains and similarly structured beta-lactones could use the same metabolic pathway as these and block the crucial enzymes, the researchers hypothesized. This assumption has been confirmed in the investigations and the scientists discovered with beta-lactone "EZ120" a substance that actually inhibits the biosynthesis of the mycomembrane and effectively kills the mycobacteria.
EZ120 works in low doses
With the help of enzyme tests and mass spectrometric investigations, Dr. Johannes Lehmann, staff member at the Chair of Organic Chemistry II at the Technical University of Munich, shows that the new inhibitor mainly blocks the enzymes Pks13 and Ag85, which play a decisive role in the development of the mycomembrane, according to the TUM announcement. In addition, EZ120 is already effective in low doses, can easily cross the mycomembranes and shows only low toxicity to human cells, the university reports.
Combined use with antibiotics
When antibiotics and EZ120 are used in combination, the scientists say that the effectiveness of the antibiotics is significantly increased. "Vancomycin, a common antibiotic, and EZ120 work very well together," says Professor Sieber. The simultaneous use enables a reduction of the antibiotic dose by more than 100 times. The expert explains that the weakening of the mycomembrane makes it easier for the antibiotics to penetrate the bacteria. According to the researchers, this could be a starting point for novel tuberculosis therapies. (fp)