Drug target identification in the obligate intracellular bacterium, Wolbachia: a chemical proteomic route to discovering novel antibacterial targets

Lymphatic filariasis and onchocerciasis are parasitic diseases that can inflict severe disability. Targeting an essential bacterial symbiont, Wolbachia, with antibiotics, leads to death of the adult worms; an important advance over currently used treatments. The Anti-Wolbachia (A·WOL) consortium has discovered thousands of potential new drugs that kill Wolbachia, but the specific targets within the bacteria are unknown. This project will utilise chemical biology techniques to identify the proteins targeted by selected anti-Wolbachia drugs with the aim of developing workflows and technologies to identify novel antibacterial targets and tools to monitor resistance.

Where does this project lie in the translational pathway? 

 

T1 – Basic Research in Medecine

 

The methodological aspects of the PhD project

Parasitology including whole organism physiology (in vivo model of Brugia malayi infection)

Pharmacology

Proteomics

Bioinformatics

Biostatistics

 

Expected outputs (publications, funding, and impact) of the PhD project

The identification of the Wolbachia protein targets of the next generation anti-Wolbachia preclinical candidates: TylAMac and AWZ1066, will be the major outcome of this project, providing proof-of-concept that target deconvolution is achievable in Wolbachia. Another outcome will be the establishment of an optimised workflow enabling future studies to be conducted with other drugs/screening hits and be potentially translatable to similar research with other bacteria.

Overall, the project will nurture a talented PhD student within a multi-disciplinary team of collaborative expertise in biology, medicinal chemistry and chemical biology to strengthen the translational science of our discovery outputs and build a solid framework for attracting income from funders.

 

External industry links or training opportunities 

The student will benefit from multiple long-standing A-WOL collaborations with industrial partners. AbbVie Pharmaceuticals, with whom we share a patent as co-inventors of oral bioavailable tylosin analogues (TylAMacsTM) will be a key partner in advising the project workflow.

Additionally the student will benefit from acessing an interdisciplinary team including in silico cheminformaticians and medicinal chemists at the University of Liverpool.

Required skills/experience/aptitudes

The project would require a high calibre biological sciences or pharmacology graduate scientist. Whilst previous laboratory experience of proteomics or other bioinformatic analytical approaches would be desirable, the student will be given full training in the various aspects of the project workflow via our interdisciplinary networks, including pharmaceutical industry in kind support.

Key publications that relate to this proposed project

1.

M. J. Taylor et al. Parasitol. 2014, 141, 119.

 

2.

K. L. Johnston et al. J. Biomol. Screen. 2014,19, 335.

 

3.

I. Chopra and M. Roberts. Microbiol. Mol. Biol. Rev. 2001, 65, 232.

 

4.

M. L. Nelson et al. J. Org. Chem. 2003, 68, 5838.

The deadline for applications is Friday 20th July 2018 23.45 BST.

More information on this programme can be found here

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