This PhD opportunity is being offered as part of the LSTM and Lancaster University Doctoral Training Partnership. Find out more about the studentships and how to apply.
| Abstract | Tuberculosis (TB) remains a major global health burden with more than 1 million deaths every year. The causative agent Mycobacterium tuberculosis is the largest killer amongst bacterial infections. There is an urgent need to develop new drugs which can shorten therapy and treat drug-resistant infections. Much recent effort has been expended in phenotypic screening to identify new molecular series for tuberculosis drug discovery and development. Along with this, a chemical genomics approach has been taken to find novel M. tuberculosis drug targets using hit compounds identified in these screens. We are interested both in developing novel drugs and in understanding how such drugs work. We have identified a novel mechanism of action for several new antibacterial classes that work via disruption of metal ion homeostasis and/or work as metal ion ionophores. We have also identified a resistance mechanism due to mutations in the Esx-3 secretion system. These mutations also give rise to low-level resistance to other tuberculosis drugs. This project will follow up on our initial observations. We have three major aims (i) to determine how these disruptions lead to bacterial death (ii) determine how mutations in Esx-3 lead to resistance and (iii) determine the clinical relevance of mutations in Esx-3. |
| Where does this project lie in the translational pathway? | T1 - Basic Research |
| Methodological Aspects | This project will use a wide variety of microbiological, molecular, and analytical techniques. It includes the following
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| Expected Outputs |
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| Training Opportunities | The student will receive training in microbiology, molecular biology and analytical chemistry with a strong translational focus. They will receive training for M. tuberculosis culture (work within containment level 3 laboratories), microbial genetics, in vitro infection models, and drug efficacy assays. They will received training for the design and analysis of experiments. Training will also include statistical analysis, and data visualization. The student will benefit from interdisciplinary supervision and collaboration with experts in microbiology, molecular biology and medicinal chemistry. They will participate in lab meetings, journal clubs, and research seminars, and have opportunities to attend specialist workshops. Professional development will include training for presentation of research at conferences, preparation of scientific manuscripts, research ethics, project management, and science communication. |
| Skills Required | background in biomedical or biological sciences, such as microbiology, biochemistry, or a related discipline. Prior experience with laboratory techniques such as microbial culture, or basic molecular biology is desirable. A background in antimicrobials or infectious disease biology would be advantageous, as would familiarity with data analysis and quantitative thinking. The student should demonstrate analytical and problem-solving abilities, attention to detail, and enthusiasm for experimental work in a containment laboratory. Good communication and teamwork skills, along with motivation to learn interdisciplinary methods and engage in translational research, will be essential for success in this project. |
| Subject Areas | Drug Discovery and Development. Neglected Tropical Diseases |
| Key Publications associated with this project |
https://pubmed.ncbi.nlm.nih.gov/31899974/ https://pubmed.ncbi.nlm.nih.gov/39331790/ https://pubmed.ncbi.nlm.nih.gov/33521468/ |