Chemical Biology Studies to Identify Potential Drug Targets in Bacteria

Supervisors: Ian Gilbert, Sarah Coulthurst

Project Description:

The aim of the project will be to discover potential new drug targets in bacteria. There is a need for new drug targets due to the ever-increasing problem of drug resistance. One of the major issues with developing new drugs for treating Gram negative bacteria is the challenge of obtaining sufficient compound exposure within the bacteria. This is due to two factors, the lack of permeability of the cell envelope and the presence of efflux pumps which remove compounds from cells. Therefore it is important to find targets which can be inhibited by compounds that penetrate the bacteria.

1. Characterisation of Hits:

The project will initiate by screening some compound libraries against the Gram negative ESKAPE pathogens (E. coli, P. aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii). We will then validate the new hits, through re-purchase and re-synthesis. Appropriate series will then undergo several rounds of chemical optimisation to establish preliminary structure activity relationships and provide further validation that the chemical hit series are specific.

2. Mode of Action Studies

Mode of action studies will then be carried out with validated chemical series. A number of techniques will be followed. These could include:

  • Resistance generation followed by whole genome sequencing
  • Chemical proteomics, either through pull-down experiments with immobilised ligands or through CETSA.

The precise range of techniques used will depend on initial data generated. Where potential targets are identified, these will need further validation.

Outputs: potential drug targets for both human and animal health.

Learning: the student will obtain training in a large number of techniques across both chemistry and biology.

Skillsets: The student will be required to carry out chemical synthesis and a variety of techniques within microbiology. This would suit someone who has a background in organic or biological chemistry and either experience or interest in cellular biology.