De novo molecular design to understand and overcome bacterial pathogens

Antimicrobial resistance (AMR) is one of the greatest health challenges of the 21st century. Infections caused by bacteria resistant to antibiotics are already responsible for around 1.27 million deaths every year, and this figure is projected to rise to 10 million annually by 2050 without effective new treatments. Gram-negative bacteria, which include 9 of the World Health Organisation’s 13 priority pathogens, are particularly difficult to treat. Their complex cell envelopes limit the entry of many antibiotics, and no new drug classes effective against them have reached the clinic in over 50 years.
This Fellowship addresses this problem by developing new strategies to both study and inhibit bacterial pathogens, focusing on targets that are important in multidrug resistant Gram-negative species. The project will focus on creating two complementary types of de novo designed molecules using recent advances in AI-based molecular design. The first are miniproteins, small and highly stable proteins that can bind with high specificity to bacterial proteins located on the surface or outside the cell envelope. The second are cyclic peptides, ring-shaped molecules that can cross bacterial membranes, allowing them to reach proteins inside the cell envelope. Together, these molecules will enable important bacterial processes to be investigated and disrupted.
The project has three main objectives:

To generate mechanistic insight by using miniproteins and cyclic peptides as molecular tools to study how bacteria respond to stress, cause disease, and resist treatment.
To identify vulnerabilities by pinpointing weak spots in bacterial proteins that could be exploited in the design of new therapies.
To demonstrate proof-of-principle inhibition by showing that designed molecules can disrupt essential bacterial processes and provide starting points for next-generation anti-infectives.

To achieve these aims, the work will combine computational design with experimental approaches in...