Beta-lactone to Attack Tuberculosis

Beta-lactone inhibits mycomenbrane biosynthesis and increases the efficiency of antibiotics to kill the bacteria.

Research teams from the Technical University of Munich (TUM), as well as Harvard University and Texas A&M University in the USA have found a new ally in the search of new strategies against life-threatening tuberculosis infections. They discovered a substance that interferes with the mycomembrane formation of the bacterium. It is effective even in low concentrations and when combined with known antibiotics their effectiveness is improved by up to 100-fold.

Among the greatest challenges when treating life-threatening tuberculosis infections is the increasing resistance to antibiotics. But the pathogen itself also makes the life of doctors difficult: its dense mycomembrane hampers the effect of many medications. A team of scientists headed by Stephan A. Sieber, Professor of Organic Chemistry at TU Munich, has discovered a substance that perturbs the formation of this membrane significantly.

Mycobacteria Response to Antibiotics Differs Based on Growth and Timing
The growth of the bacteria and the phase of the cell division cycle that bacteria were in when exposed to the antibiotic had an impact on the response to drugs.

‘Beta lactone EZ120 inhibits the biosynthesis of the mycomembrane and kills mycobacteria effectively.’

The mycomembrane of the tuberculosis pathogen Mycobacterium tuberculosis consists of a lipid double layer that encapsulates the cell wall, forming an exterior barrier. Structural hallmarks are mycolic acids, branched beta-hydroxy fatty acids with two long hydrocarbon chains.

The team hypothesizes that similarly structured beta lactones could "mask" themselves as mycolic acid to enter the mycolic acid metabolic pathways and then block the decisive enzymes.

Helpful disrupter

Inhaled Corticosteroids Increase Risk of Non-tuberculous Mycobacterial Disease
Non-tuberculous mycobacteria are widely dispersed and increasingly found in the environment. In most cases, they are harmless.

In the context of an extensive search, the interdisciplinary team of scientists hit the bullseye with the beta lactone EZ120. It does indeed inhibit the biosynthesis of the mycomembrane and kills mycobacteria effectively.

Using enzyme assays and mass spectroscopy investigations, Dr. Johannes Lehmann, a researcher at the Chair of Organic Chemistry II at TU Munich, demonstrated during his doctoral work that the new inhibitor blocks especially the enzymes Pks13 and Ag85, which play a key role in the development of mycomembranes.

Tuberculosis and Other Mycobacteria can be Killed With Vinegar
Acetic acid, the active ingredient in vinegar, is effective in killing mycobacteria, even the highly drug-resistant ones like Mycobacterium tuberculosis, revealed a team of researchers.

EZ120 is effective even in low doses, easily passes the mycomembrane and exhibits only low toxicity to human cells. The combined application of this substance with known antibiotics showed a synergistic effect leading to significantly increased effectiveness."Vancomycin, a common antibiotic, and EZ120 work together very well," says Prof. Sieber, who heads the Chair of Organic Chemistry II. "When used together, the dose can be reduced over 100-fold.

"The scientists suspect that disrupting the mycomembrane enables antibiotics to enter the bacteria more easily. This is a new mode of action and might be a starting point for novel tuberculosis therapies.

'Survival Gene' Suppresses Mutation Rates in Tuberculosis Bacteria
A key 'survival gene' that prevents strains of tuberculosis (TB) from mutating into drug-resistant 'superbugs' have been discovered.

Source-Eurekalert