Assessing risks of resistance to novel antimicrobials targeting Pseudomonas aeruginosa
LEAD SUPERVISOR: Professor Craig MacLean, Department of Biology
Co-supervisor: Dr Rachel Wheatley, Department of Biology
Co-supervisor: Dr Mathew Stracy, Department of Biology
Commercial partner: Bactobio Ltd, London
Antibiotic resistance has emerged as an important threat to human health, and there is a clear need to develop new drugs that are active against multi-drug resistant bacterial pathogens. Resistance spreads in pathogen populations as a result of evolutionary and ecological processes, but risks of resistance evolution are not adequately accessed during pre-clinical development, hindering the development of novel antibiotics.
80% of today's antibiotics derive from the ~1% of bacteria that can be cultured using standard techniques. The remaining 99% represent the world's largest bioresource and an untapped source of chemically diverse antibiotics with novel modes-of-action.
Bactobio, the commercial partner, have developed a proprietary platform that uses synthetic biology, next-generation sequencing, and machine-learning to cultivate previously unculturable bacteria and screen them for novel antibiotics. Bactobio have captured >1,700 novel species of bacteria from diverse phyla with around 10% producing antibiotics against critical priority pathogens identified by the WHO, including Pseudomonas aeruginosa.
The goal of this project will be to assess the potential for P.aeruginosa to evolve resistance to novel antimicrobials that have been isolated by Bactobio. This will involve:
(i) Screening a large library of clinical isolates of P.aeruginosa, including epidemically successful MDR and XDR strains, to test for pre-existing resistance and tolerance to novel antibiotics.
(ii) Using experimental evolution to assess the potential for P.aeruginosa to evolve de novo resistance and tolerance to novel antibiotics by assessing the (a) mutation rate to resistance/tolerance, (b) fitness costs of resistance/tolerance and (c) stability of resistance/tolerance and (d) potential to evolve compensatory adaptations to offset the cost of resistance.
(iii) Identifying the molecular mechanisms of resistance/tolerance to novel antibiotics by whole genome sequencing of evolved resistant isolates and mutation reconstruction.
This project will build on Oxford’s expertise in the evolutionary biology of antibiotic resistance and Bactobio’s expertise in drug discovery. One of the research goals of the academics involved in the project has been to use evolutionary principles to understand when resistance will spread in pathogen populations, and when it will be lost. The applicants have worked on this problem using antibiotics that are already in clinical use, where resistance is very common. This project will provide the applicants with a unique opportunity to work on novel antibiotics, and to assess the potential for resistance to evolve before the antibiotics are used in clinical settings, which is currently not being done by pharma. Reciprocally, this will provide the commercial partner with invaluable insights into the extent to which the drugs that they are developing can be compromised by pathogen evolution. This may help them to prioritise their drugs for development and identify drugs that may be suitable for chemical modification to help offset the risk of resistance. As a new collaboration between University of Oxford and Bactobio, this project will also foster collaborations for discovery science, bringing together Bactobio’s expertise in Drug Discovery and Maclean lab expertise in understanding resistance in bacterial evolution.
Apply using course: DPhil in Biology