Towards new antibacterial drugs to treat infections caused by multidrug-resistant bacteria: identification and characterization of novel natural produ

Summary

Antibiotics make possible the treatment and cure of life-threatening bacterial infections and have added over a decade to the 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. To address this problem, it is imperative that new antibiotics are discovered as matter of urgency.

The best-validated source of antibiotics is nature, with most of our existing antibiotic armamentarium deriving from soil microorganisms. However, this source stopped routinely yielding novel compounds decades ago and was largely abandoned in the search for new antibiotics. Viewed through the lens of our current knowledge, this was not because this source had been comprehensively mined – far from it, in fact– but simply that continuing to screen the same types of microorganisms in the same way will not deliver new antibiotics (“if you do what you have always done, you get what you always got”).

Our view is that nature remains far and away the best place to look for new antibiotics, though strategic innovation will be essential to do so effectively. The O’Neill lab is working to systematically address the pit-falls and bottle-necks in natural product antibiotic discovery, identifying new sources/ types of microorganism for testing, creating novel screening tools for improved detection of antibiotics, and evolving approaches that allow rapid assessment of the chemical/ functional novelty and therapeutic potential of these compounds .

The proposed studentship will not only work to establish innovative approaches to antibiotic discovery, but will also deploy these to identify new drug candidates effective against the most problematic types of multi-drug resistant bacteria. Building on exciting recent findings in our lab, this project will utilise ichip technology to recover microorganisms new to science from a variety of sources, and will screen these for antibiotic production using novel tools/ approaches that will be created or evolved over the course of the study. Collectively, this project will rejuvenate and accelerate the discovery of new antibiotics from nature, thereby helping to address the global challenge of AMR and providing the appointed student with cutting-edge, multidisciplinary training in bacteriology, molecular biology and antibiotic discovery.

Please see the O’Neill lab website for more information about what we do, and links to our published work:

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

References

• 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.
• Galarion LH, Mohamad M, Alzeyadi Z, Randall CP, O'Neill AJ (2021). A platform for detecting cross-resistance in antibacterial drug discovery. Journal of Antimicrobial Chemotherapy, 76: 1467-1471
• Nass NM, Farooque S, Hind C, Wand ME, Randall CP, Sutton JM, Seipke RF, Rayner C, O'Neill AJ (2017). Revisiting unexploited antibiotics in search of new antibacterial drug candidates: the case of gamma-actinorhodin. Scientific Reports, 7: 17419

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