Activating antibiotic production: High-throughput genetics identification and characterisation of novel antibiotics at University of Nottingham on FindAPhD.com

This project is no longer listed on FindAPhD.com and may not be available.

Click here to search FindAPhD.com for PhD studentship opportunities

Dr Jack Bryant No more applications being accepted Competition Funded PhD Project (Students Worldwide)

Nottingham United Kingdom Bacteriology Biochemistry Genetics Microbiology Molecular Biology Structural Biology

School of Medicine, University of Nottingham

About the Project

Drug-resistant bacterial infections cause 1.27 million deaths annually and antimicrobial resistance is one of the biggest threats to global public health. To further compound this issue, no new antibiotic classes have made it to market since 1987. Therefore, there is an urgent need for discovery of new antibiotics to address this issue.

One of the most recently identified antibiotics, darobactin, was identified in the insect-killing bacteria Photorhabdus khanii. However, discovery of darobactin was hindered by the fact that the bacterium does not express the antibiotic under laboratory conditions and the trigger for expression is unknown4. This is a common problem in antibiotic and secondary metabolite discovery.

Using high-throughput transposon mutagenesis, we will develop a genome-wide, high-throughput assay for induction and identification of silent antimicrobial encoding gene clusters in Photorhabdus species. We will then identify the antimicrobials by mass spectrometry and investigate their modes of action by using a combination of high-throughput genetics, high-resolution real-time microscopy, protein purification, biochemistry and structural biology. Following this, we will assess the effects on a range of clinically relevant bacteria. This work will act as a template for the activation and identification of antimicrobials from diverse bacterial species.

Funding Notes

Competition Funded PhD Project (Students Worldwide) Closing date 10 January 2025 midday GMT

This is a fully funded Medical Research Council (MRC) studentship. Stipend and tuition fees are paid for 4 years at UKRI rates as well as there being a budget for project consumables, travel and a laptop to be purchased. The funder, UKRI, allows us to appoint up to 30% overseas students.

Enquiries

Project Enquiries to [Email Address Removed] Faculty of Medicine & Health Sciences

Programme enquiries to [Email Address Removed]

To apply please refer to https://more.bham.ac.uk/mrc-aim/phd-opportunities/ for project opportunities and application form

References

1 Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 399, 629-655 (2022). https://doi.org:10.1016/s0140-6736(21)02724-0
2 O'Neill, J. Tackling drug-resistant infections globally: final report and recommendations. (Government of the United Kingdom, 2016).
3 Miethke, M. et al. Towards the sustainable discovery and development of new antibiotics. Nature Reviews Chemistry 5, 726-749 (2021). https://doi.org:10.1038/s41570-021-00313-1
4 Imai, Y. et al. A new antibiotic selectively kills Gram-negative pathogens. Nature 576, 459-464 (2019). https://doi.org:10.1038/s41586-019-1791-1
5 Hoskisson, P. A. & Seipke, R. F. Cryptic or Silent? The Known Unknowns, Unknown Knowns, and Unknown Unknowns of Secondary Metabolism. mBio 11, 10.1128/mbio.02642-02620 (2020). https://doi.org:doi:10.1128/mbio.02642-20
6 Yasir, M. et al. TraDIS-Xpress: a high-resolution whole-genome assay identifies novel mechanisms of triclosan action and resistance. Genome Res 30, 239-249 (2020). https://doi.org:10.1101/gr.254391.119
7 Wang, M. et al. Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking. Nat Biotechnol 34, 828-837 (2016). https://doi.org:10.1038/nbt.3597
8 Petras, D. et al. GNPS Dashboard: collaborative exploration of mass spectrometry data in the web browser. Nat Methods 19, 134-136 (2022). https://doi.org:10.1038/s41592-021-01339-5