Exploration of the TPP riboswitch as a new target for antibiotics
Our EXPLORE network application aiming at targeting the TPP riboswitch for hit discovery for new antibiotics will receive funding from JPI-AMR! Other partners in the network are Daniel Lafontaine (Université de Sherbrooke, Canada), Matthias Mack (Mannheim University of Applied Sciences, Germany), Petr Bartunek (CZ-OPENSCREEN, Czech Republic), Bengt Erik Haug (University of Bergen Norway) and Gints Smits (Latvian Institute of Organic Synthesis, Latvia). Ruth Brenk will the the project coordinator.
And this is what we are trying to do:
The WHO has stated a critical or high need for antibiotics against bacterial pathogens like E. coli, K. pneumoniae, A. baumannii, P. aeruginosa, S. aureus among others. In order to develop new antibiotics against these bacteria, we have to “hit them where it hurts them” meaning that we have to interfere with a process that is essential for the bacteria to survive. One potential target is the thiamine pyrophosphate (TPP) riboswitch. A riboswitch is part of the mRNA and regulates the expression of genes by binding small molecules. In the case of the TPP riboswitch, the natural ligand is TPP, a compound related to vitamin B1. If the cell has enough vitamin B1, TPP binds to the riboswitch and regulates the expression of genes important for vitamin B1 uptake and synthesis down. As a consequence, no more vitamin B1 is synthesized. Our goal is to find another small molecule that binds to the TPP riboswitch to trick the bacteria into believing that they have enough vitamin B1 and thus starve them of this essential co-factor which will ultimately lead to their death. Such a molecule can then be the starting point for developing urgently needed antibiotics.