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

Summary

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 Based on exciting proof of principle in very recent (as yet unpublished) work from our joint medicinal chemistry-biology effort, we have successfully undertaken rational optimisation of intracellular accumulation and target binding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

References

These references provide a general flavour of our research on antibacterial drug discovery and AMR - they do not describe work directly related to this project.

• Galarion LH, Mitchell JK, Randall CP, O'Neill AJ (2023) An extensively validated whole-cell biosensor for specific, sensitive and high-throughput detection of antibacterial inhibitors targeting cell-wall biosynthesis. Journal of Antimicrobial Chemotherapy, 78: 646-655
• Mohamad M, Nicholson D, Saha CK, Hauryliuk V, Edwards TA, Atkinson GC, Ranson NA, O’Neill AJ (2022). Sal-type ABC-F proteins: intrinsic and common mediators of pleuromutilin resistance by target protection in staphylococci. Nucleic Acids Research, 50: 2128-2142
• Orritt KM, Feng L, Newell JF, Sutton JN, Grossman S, Germe T, Abbott LR, Jackson HL, Bury BKL, Maxwell A, McPhillie MJ, Fishwick CWG (2022) De novo design of type II topoisomerase inhibitors as potential antimicrobial agents targeting a novel binding region. RSC Medicinal Chemistry, 831-839 13.7
• Lang PA, Parkova A, Leissing TM, Calvopiña K, Cain R, Krajnc A, Panduwawala TD, Philippe J, Fishwick CWG, Trapencieris P, Page MGP, Schofield CJ, Brem J (2020) Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from Escherichia coli, Biomolecules. 10.6
  

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