Drug discovery and repurposing to target key bacterial respiratory complexes
Lead Research Organisation:
University of Kent
Department Name: Sch of Biosciences
Abstract
Rationale
Antimicrobial resistance remains, 'one of the most urgent health threats of our time', accelerated by indiscriminate antimicrobial use during the COVID pandemic. Tuberculosis accounts for 1 in 3 deaths from antimicrobial resistance. New approaches are urgently needed. The overarching goal of this project is to repurpose existing drugs and identify novel inhibitors to target bacterial protein complexes that are important during infection. The protein complex of interest is the cytochrome bd complex, which is found in a broad range of bacterial pathogens and is not present in humans, making this an excellent choice of drug target. This work is particularly timely given the recent publication of the structures of cytochrome bd from E. coli and Mycobacterium tuberculosis.
Approaches and preliminary work
The Shepherd and Wass labs have developed a computational pipeline for in silico drug screening and have identified hundreds of compounds (from thousands of molecules in a number of libraries) that are likely to target cytochrome bd. Additionally, the host lab has a variety of key mutant strains that are required for drug efficacy assays, which include oxygen electrode measurements, viability assays, and a recently-developed high-throughput fluorescence technique to measure oxygen consumption. The Waddell lab has extensive expertise in Mycobacterium tuberculosis antimicrobial susceptibility testing and the investigation of drug mode of action using transcriptomic and genomic approaches.
The student will employ in silico screening approaches to identify hits and experimentally quantify compound efficacy using the aforementioned suite of techniques. Resistance-causing mutations will also be investigated. We will focus on multidrug-resistant E. coli and M. tuberculosis with scope to expand to other ESKAPE pathogens.
Potential Impact
This work has the potential for transformative change in the treatment of infectious diseases, discovering new inhibitors and repurposing existing drugs
to treat bacterial infections that are resistant to all conventional antibiotics.
Antimicrobial resistance remains, 'one of the most urgent health threats of our time', accelerated by indiscriminate antimicrobial use during the COVID pandemic. Tuberculosis accounts for 1 in 3 deaths from antimicrobial resistance. New approaches are urgently needed. The overarching goal of this project is to repurpose existing drugs and identify novel inhibitors to target bacterial protein complexes that are important during infection. The protein complex of interest is the cytochrome bd complex, which is found in a broad range of bacterial pathogens and is not present in humans, making this an excellent choice of drug target. This work is particularly timely given the recent publication of the structures of cytochrome bd from E. coli and Mycobacterium tuberculosis.
Approaches and preliminary work
The Shepherd and Wass labs have developed a computational pipeline for in silico drug screening and have identified hundreds of compounds (from thousands of molecules in a number of libraries) that are likely to target cytochrome bd. Additionally, the host lab has a variety of key mutant strains that are required for drug efficacy assays, which include oxygen electrode measurements, viability assays, and a recently-developed high-throughput fluorescence technique to measure oxygen consumption. The Waddell lab has extensive expertise in Mycobacterium tuberculosis antimicrobial susceptibility testing and the investigation of drug mode of action using transcriptomic and genomic approaches.
The student will employ in silico screening approaches to identify hits and experimentally quantify compound efficacy using the aforementioned suite of techniques. Resistance-causing mutations will also be investigated. We will focus on multidrug-resistant E. coli and M. tuberculosis with scope to expand to other ESKAPE pathogens.
Potential Impact
This work has the potential for transformative change in the treatment of infectious diseases, discovering new inhibitors and repurposing existing drugs
to treat bacterial infections that are resistant to all conventional antibiotics.
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/T008768/1 | 01/10/2020 | 30/09/2028 | |||
| 2750000 | Studentship | BB/T008768/1 | 01/10/2022 | 30/09/2026 |