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Structural Biology of Antimicrobial Targets

Primary Supervisor: Dr Lona Alkhalaf, Department of Chemistry

Secondary supervisor: Professor Greg Challis

PhD project title: Structural Biology of Antimicrobial Targets

University of Registration: University of Warwick

Project outline:

Antimicrobial resistance (AMR) is a serious and imminent threat, as the number of newly identified antibiotics falls and resistance to existing antibiotics increases. Historically, natural products have been the primary source of novel antibiotics, and recent advances in genome sequencing and bioinformatics have once again put them at the forefront in the fight against AMR. However, once a natural product has been established as an effective agent in antimicrobial screens, its molecular target(s) must be identified. This knowledge is essential to fully understand the cellular mechanism of the antibiotic, predict likely routes to resistance and rationally design structural analogues. Fortunately, biosynthetic gene clusters, which direct the biosynthesis of natural products, often contain homologues of target genes as a mechanism of self-resistance, allowing prediction of likely bacterial targets.

The project will involve validation and structural characterisation of the proposed targets for two novel natural product antibiotics encoded by the same gene cluster. The two structurally-related natural products are proposed to target two discrete processes in bacterial protein production. This dual mechanism of action would be a remarkable naturally occurring method to overcome development of resistance, as any susceptible bacteria would have to develop mutations in two genes concurrently. The PhD project will involve: 1) Establishing the proposed targets are responsible for self-resistance in the producing strain by expressing them in an antibiotic sensitive heterologous host. 2) Overproduction and purification of the proposed molecular targets; 3) Structural characterisation of binding at a molecular level using X-ray crystallography; and 4) In silico docking studies to inform rational design of structural analogues.

References:

BBSRC Strategic Research Priority: Integrated Understanding of Health: Pharmaceuticals & Understanding the Rules of Life: Structural Biology

Techniques that will be undertaken during the project:

Contact supervisor for information regarding techniques.

Contact: Dr Lona Alkhalaf, University of Warwick