Periodic Reporting for period 2 - PP-MAGIC ((Photo-)Control of Persisters: Targeting the Magic Spot)
Reporting period: 2021-09-01 to 2023-02-28
The development of persistence is regulated amongst others by small molecules which are called the magic spot nucleotides. We want to investigate, how magic spot nucleotides regulate bacterial metabolism and identify ways to interfere with this regulation so that metabolic shutdown of bacteria will not work anymore. Under such conditions, either additional antibiotics or even the patients immune system alone might clear the infection.
Overall, we address an important societal problem, which is the threat by multidrug-resistant and persistent bacteria. We want to address this problem by developing a chemical biology medicinal chemistry approach to understand and manipulate the magic spot nucleotides. This requires combination of synthetic chemisrtry, analytical chemistry, biochemistry, and microbiology, which we aim to achieve in this project.
Ultimately, we are aiming for a deeper understanding of how the magic spot nucleotides operate and how we can manipulate them to discover new antibiotics for society.
We will now start to study the efficiency of our new synthetic inhibitors and see if they affect bacterial growth, metabolic shutdown, and viability. This should lead to new structures for potential antibiotics that could be developed as new pharmaceutical entities.
We have also developed a direct uptake system for MSN into bacteria. This will enable a plethora of experiments by simply incubating bacteria with compounds of interest. So far, MSN uptake was precluded due to the highly polar nature of MSN.
Our pull-down studies with modified photoaffinity pull-down MSN has enabled us to delineate new protein interactors, which are currently under evaluation. This will provide insights into how MSN are regulated and how (and which) cellular processes are regulated by them.