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Giving old drugs a new purpose for TB therapy

Principal Supervisor: Dr Luke Alderwick - School of Biosciences

Co-supervisor: Dr Apporva Bhatt

PhD project title: Giving old drugs a new purpose for TB therapy

University of Registration: Birmingham

Project outline:

Background

The global incidence of Tuberculosis (TB) continues to burden humankind with approximately 9 million new cases annually. TB is a treatable disease with Directly Observed Treatment Short-course (DOTS); a cocktail of 4 drugs that TB patients take over a period of 6 months. However, the last two decades has seen an alarming rise in the incidence of multi drug resistant TB (MDR-TB) and extensively drug resistant TB (XDR-TB). Whilst new anti-TB drugs are urgently needed, the timescales and hurdles involved in developing new drugs from discovery to FDA approval are dissentient towards this ultimate goal.

Project Objectives

This project involves screening a ~1200 library of FDA approved drugs against fast and slow growing strains of mycobacteria under a variety of growth conditions. Compounds will be screened in the presence and absence of the front line anti-TB drugs to look for potentiators of the current therapy. Any hits that emerge from this screen have the potential to rapidly progress through the “developmental pipeline” and enter the clinic, thus reaching TB patients faster than developing a new compound from scratch.

Scientific Approach

  1. Using the High Throughput Screening platform in the Birmingham Drug Discovery Facility housed in the IMI screen the ~1200 compounds from the FDA library against M. smegmatis and M. bovis (BCG) under a variety of growth conditions (nutrient limited, high oxygen tension etc). Screens will be conducted ± current front line drugs (Ethambutol, Isoniazid, Rifampicin and Pyrazinamide).
  2. Selected “hits” that emerge from the above screen(s) will then be tested against the human pathogen M. tuberculosis H37Rv in the BSL-3 laboratory in the IMI.

Conduct mode of action (MoA) studies on selected hits to understand how compounds can potentiate the current drug regimen.

BBSRC Strategic Research Priority: Molecules, cells and systems

Techniques that will be undertaken during the project:

Screening

All screening activities will be carried out using a fully automated robotic screening platform in the Birmingham Drug Discovery Facility housed in the IMI. Screening activities will be under the supervision and guidance of Dr Luke Alderwick. Specific skills gained include:

  1. Culture of mycobacterial model organisms (M. smegmatis and M. bovis (BCG)).
  2. Anti-microbial screening using state-of-the-art HTS platforms (MIC, MBC testing).
  3. Data analysis (chemoinformatics) of large data sets.
  4. Synergy studies (design of chequerboard assays).

Mode of Action Studies

We will make use of the biochemical and molecular genetic expertise of the TB research group to investigate how hits affect growth at a molecular level. These studies will be supervised by Dr Apoorva Bhatt and Dr Luke Alderwick.

  1. Generation of laboratory resistant mutants to hit compound/compound combinations.
  2. Extraction of genomic DNA for whole genome sequencing studies (genomes will be sequenced if mutants are isolated within the timeframe of the project).
  3. Macromolecular labeling of cultures to identify MoA (i.e. inhibition of DNA, RNA, Protein, Cell wall biosynthesis synthesis).

BSL-3 training

Safe handling of pathogenic M. tuberculosis H37Rv in a BSL-3 containment laboratory will be under the strict supervision and guidance of Dr Apoorva Bhatt and Dr Luke Alderwick.

  1. Culture of M. tuberculosis H37Rv in a BSL-3 environment. (Training in BSL-3 containment). Anti-microbial testing of compounds in both liquid and solid media.

Contact: Dr Luke Alderwick, University of Birmingham