Bedaquiline induces the dormancy regulon

Wednesday, February 26th, 2014 by hinrich

Structure of TMC207/R207910

We have just published in “Nature Communications” new results that may contribute to our understanding of the working mechanism of our compound Bedaquiline (TMC207/R207910) against Mycobacterium tuberculosis. We have especially investigated why it takes more time for the compound to kill the bacteria ("[...] early bactericidal activity during the first week of chemotherapy is minimal").

Identifying such early bactericidal activity has been used for many decades in the clinic as an indicator for the efficacy of a new compound. Accordingly, if the early effects are low, this has been seen as a disadvantage for the further development of a compound. An obvious reason is that clinical trials need to last longer to proof efficacy - which is of course more expensive.

Our data suggests that as a consequence of treatment with Bedaquiline - which inhibits the ATPsynthase of the TB bacteria and thereby reduces the available energy supply - the bacteria adjust aspects of their metabolism in an attempt to survive the energy shortage. Furthermore, using Affymetrix microarrays we show data that suggest an induction of the dormancy regulon. These findings may provide us with a hypothesis how the bacteria can survive the initial phase of drug exposure.

Reference: Delayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism

Posted in Tuberculosis