Broadening the spectrum of antibacterial drugs to tackle multi-drug resistant Gram-negative pathogens

Antibiotics make possible the treatment and cure of life-threatening bacterial infections and have added over a decade to average human lifespan. Unfortunately, the utility of these drugs is being rapidly eroded as pathogenic bacteria evolve to resist their effects; in 2019, antimicrobial resistance (AMR) killed ~1.3 million people worldwide, and this figure is set to rise to 10 million by 2050. The situation is particularly grave in the case of Gram-negative (G-VE) pathogens, which, in contrast to Gram-positive (G+VE) bacteria, are intrinsically insusceptible to many classes of antibacterial drug owing to the permeability barrier presented by the outer membrane and the action of efflux transporters that pump drugs out of the cell.  

This project will develop much-needed novel anti-G-VE agents through rational, structure-guided modification of established antibacterial drug classes that currently only show clinically useful activity against G+VE bacteria. Although analogue improvement of antibacterial drugs is a proven strategy, it has not typically been successful in expanding the activity of anti-G+VE agents to encompass G-VEs; however, it represents a potentially powerful approach in this context that could circumvent many of the confounders encountered in discovery programmes and dramatically shorten the lead time to new drugs. Based on exciting proof of principle in very recent (as yet unpublished) work from our joint medicinal chemistry-biology effort, we have successfully undertaken rational optimisation of intracellular accumulation and target binding to build potent anti-G-VE activity into a drug class that previously showed none – our lead compound is now undergoing evaluation of therapeutic efficacy in vivo.

The present study will seek to further increase the anti-GVE potency of the drug class in question, as well as extending this powerful approach to other clinically deployed classes that possess untapped potential for expansion of antibacterial spectrum (of which there are several). We will exploit our structural and mechanistic understanding of antibacterial drug targets – and of the biological processes influencing antibiotic accumulation inside G-VE bacteria – to design and synthesise new analogues of known classes. The resulting compounds will undergo extensive biological evaluation in vitro and in vivo to assess their antibacterial potency/ efficacy against a range of G-VE pathogens, and to confirm improved target binding and intracellular accumulation.

Collectively, this project will generate new knowledge, insight and antibacterial molecules, all of which can contribute towards addressing the growing global challenge of AMR. The appointed student will benefit from cutting-edge, multidisciplinary training in medicinal chemistry, molecular bacteriology and antibiotic discovery.

Please see our websites for more information about the work that we do, and links to our publications:

https://biologicalsciences.leeds.ac.uk/molecular-and-cellular-biology/staff/119/professor-alex-o-neill

https://eps.leeds.ac.uk/chemistry/staff/5234/dr-martin-mcphillie

https://eps.leeds.ac.uk/chemistry/staff/4172/professor-colin-fishwick

Eligibility: 

You should hold a first degree equivalent to at least a UK upper-second class honours degree or a MSc degree in a relevant subject; this project would suit someone with a background in organic or medicinal chemistry and a strong interest in drug discovery. Additional experience of conducting research in a multidisciplinary setting is highly desirable. Upon completion of the PhD, the successful candidate will be uniquely equipped for high-demand careers within academia or industry with desirable skills in drug discovery.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The Faculty of Biological Sciences minimum requirements in IELTS and TOEFL tests are:

• British Council IELTS – score of 6.0 overall, with no element less than 5.5
• TOEFL iBT – overall score of 87 with the listening and reading element no less than 20, writing element no less than 21 and the speaking element no less than 22.

How to apply:

To apply for this project applicants should complete an online application form and attach the following documentation to support their application. 

• a full academic CV
• degree certificate and transcripts of marks
• Evidence that you meet the University’s minimum English language requirements (if applicable).
• Evidence of funding

To help us identify that you are applying for this project please ensure you provide the following information on your application form;

• Select PhD in Biological Sciences as your programme of study
• Give the full project title and name the supervisors listed in this advert