Til bevillingsoversigt

On the quest of developing antibiotics with new mode of action

Carlsberg Foundation Visiting Fellowships at University of Oxford

What

This project aims to elucidate the mechanism of action of a natural product antibiotic by means of quantitative proteomics. When a molecule binds to a proteins, more often than not, the protein melting temperature changes due to thermodynamic stabilisation. Thermal stability profiling can measure these subtle changes on a proteome wide level, allowing to dissect each protein involved in binding the natural product. Ultimately, this projects aims to characterise the mode of action of the antibiotic in order to expand the druggable antibiotic space and keep antimicrobial resistance at bay.

Why

Understanding the interaction of an antibiotic with its protein target is fundamentally important not just with respect to understanding its mode of action, but also in order to discover potentially new "Achilles' heels" in bacteria. Thermal stability profiling has emerged as a tool to identify the direct target of a drug in living cells. This information is, however, just the tip of the iceberg, and thermal stability profiling has the potential to characterize the full interaction network of the target protein upon chemical perturbation - meaning thermal stability profiling allows to paint and map out the complete downstream biological pathway. Now, applying this approach to antibiotics might identify less obvious targets for antibiotic development.

How

Initial work will rely on the chemical synthesis and the isolation of the natural product and synthetic analogues to map the structure-activity relationship (SAR). Subsequent biological evaluation and thermal stability profiling will give insight into the SAR of the natural product and thermal stabilty profiling will determine the molecular target. Subsequent target validation experiments by alternative methods, such as pull-down experiments, will independently confirm the target of the natural product. Ultimately, identification of the protein target and its biological role in the bacterial cell may become a new attractive target for antibiotic development.

SSR

During the last two years the world has witnessed what impact infectious disease can have on modern life. This project seeks to counter the inevitable rise of another pandemic by elucidating new mechanisms to fight pathogenic disease.