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 structural biology, biophysics, and microbiology. Molecules will be designed in silico, produced in the laboratory, characterised using structural and biophysical techniques, and applied to live pathogenic bacteria to assess their functional effects. Proof-of-concept data already demonstrate the feasibility of this approach, providing a solid foundation for the proposed work.
The research will benefit academics, clinicians, and industry. For academic researchers, it will provide new molecular tools to investigate poorly understood systems within the bacterial cell envelope, helping to explain how pathogens adapt and survive in the host. For clinicians and patients, it will generate potential new treatment strategies against infections that are currently difficult to treat. For industry, it will deliver molecules and design approaches that could be taken forward in biotechnology and pharmaceutical pipelines.
New treatment options could reduce mortality, shorten hospital stays, and lower healthcare costs. Molecules used as research tools will also identify new weaknesses in bacterial physiology, laying the foundations for future antimicrobial research.
In summary, this Fellowship will deliver new classes of miniproteins and cyclic peptides that act as both research tools and as potential therapeutics against multidrug resistant bacteria. The work will generate fundamental insights into bacterial survival and virulence, uncover new therapeutic vulnerabilities, and establish computational design workflows to combat bacterial AMR.