Identifying novel small molecule inhibitors of mycobacteria using a high throughput chemical-genetic interaction screening platform.

Key information

Application close date
07 February 2023, 11:59 GMT
Hours per week
36 (full time)
Application guidance
Posted 22 December 2022

Research topics

Biochemistry & Proteomics Chemical Biology & High Throughput Computational & Systems Biology Gene Expression Genetics & Genomics Infectious Disease Metabolism
Background texture taken from the lab imagery.

This is a summer student position supervised by Valwynne Faulkner from Eachan Johnson's lab. 

Introduction to the Science

In our lab, we develop and use chemical-biology and genetic tools to study clinically relevant pathogenic bacteria. Using a system wide approach we define gene functions, map gene networks, and explore how pathogenic bacteria infect their hosts and develop resistance to antibiotics.

About the Project

Mycobacterium tuberculosis is the bacteria that causes tuberculosis and kills ~4000 people daily. Increasing incidences of drug resistance pose challenges for tuberculosis treatment and control. Therefore, identifying novel drug targets and developing faster acting therapies with reduced drug-selective pressures could reduce the global burden of infection. 

This project aims to use a library of essential gene mutants, constructed using CRISPRi/dCas9 technology [1], to discover novel therapeutic targets. The prospective candidate will challenge a Mycobacterium smegmatis CRISPRi mutant library with a library of small compound molecules. PROSPECT [2], a platform for large-scale chemical-genetic interaction screening, will be used to identify chemical inhibitors of the mutants to define new targets of small compounds.

The successful candidate will be provided training in:

  • Designing experiments
  • Microbiology techniques
  • Molecular microbiology techniques, including CRISPRi/dCas9 technology
  • Performing high-throughput phenotypic assays
  • Screening small compound libraries in bacteria
  • Computational analysis

About You

This project will suit a candidate studying biomedical sciences, biochemistry, medicine, or any other biological sciences degree. Previous experience in microbiology, molecular biology techniques or computational analysis is not required. However, a keen interest in microbial genetics, antibiotic resistance or chemical biology is required.

References

1.         Bosch, B., DeJesus, M.A., Poulton, N.C., Zhang, W., Engelhart, C.A., Zaveri, A., . . . Rock, J.M. (2021)

            Genome-wide gene expression tuning reveals diverse vulnerabilities of M. tuberculosis.

            Cell 184: 4579-4592.e4524. PubMed abstract

2.         Johnson, E.O., LaVerriere, E., Office, E., Stanley, M., Meyer, E., Kawate, T., . . . Hung, D.T. (2019)

            Large-scale chemical-genetics yields new M. tuberculosis inhibitor classes.

            Nature 571: 72-78. PubMed abstract