AIMMS researchers contribute to new insights into how antibiotics kill bacteria

An international consortium including AIMMS researchers Holger Lill and Dirk Bald investigated how a newly approved anti-tuberculosis drug can kill tuberculosis bacteria.

07/19/2018 | 11:51 AM

The results of this study were published in Proceedings of the National Academy of Science USA on June 25th.  

Multi-drug resistant tuberculosis poses a serious health threat throughout the world. Bedaquiline is the first FDA approved drug for the treatment of multi-drug resistant tuberculosis in over 40 years. In 2007, researchers from Jansen Pharmaceuticals (developer of bedaquiline) together with AIMMS researchers Dirk Bald and Holger Lill showed that bedaquiline prevents growth of Mycobacterium tuberculosis by inhibiting ATP synthase, one of the cell’s most important energy providers. This finding established energy metabolism and ATP synthesis as an unexpected new frontier in the discovery of antibacterials.

Killing mechanism

For effective new antibacterial drugs bactericidal activity is expected, i.e. the drug is expected to not only prevent bacterial growth but also to kill the pathogenic bacteria. Dirk Bald and Holger Lill (both Structural Biology) joined research teams from New Zealand and the United States to elucidate the mechanism of killing by bedaquiline. It turned out that killing by this drug is not only associated with inhibition of the drug’s main target, ATP synthase, but also with breakdown of the ion equilibrium across the bacterial cytoplasmic membrane. The combination of these two mechanisms may enable very efficient killing by bedaquiline.

This result contributes to understanding of how antibacterials work and may provide input for the design of effective, bactericidal new antibiotics.