Elucidating the molecular mechanisms of intrinsic antibiotic resistance in bacterial pathogens

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. The O’Neill laboratory at Leeds is actively pursuing several complementary approaches to better understand and address this phenomenon, with a major focus on understanding the mechanisms that allow ’superbugs’ to resist the effects of antibiotics.

Studies into antibiotic resistance mechanisms have typically focused on acquired resistance – in other words, evolved traits that become selected in bacteria by antibiotic exposure. However, many bacteria are inherently resistance to particular antibiotic classes, a phenomenon known as intrinsic resistance. The latter is currently under-studied, though it has become clear that analysis of such intrinsic resistance mechanisms can offer profound fundamental insights into the biology of AMR and provide valuable strategic intelligence to inform the discovery of newer generations of antibiotics. This studentship will investigate the genetic and biochemical basis for intrinsic resistance to a variety of important antibacterial drugs in key pathogenic bacteria, employing a suite of cutting-edge approaches in molecular biology to do so. Please see reference I below for an example of intrinsic resistance and the kinds of tools we have at our disposal to study it.

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

• I. 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
• II. Crowe-McAuliffe C, Murina V, Turnbull KJ, Kasari M, Mohamad M, Polte C, Takada H, Vaitkevicius K, Johansson J, Ignatova Z, Atkinson GC, O’Neill AJ, Hauryliuk V, Wilson DN (2021). Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens. Nature Communications, 12: 3577
• III. Wilson DN, Hauryliuk V, Atkinson GC, O'Neill AJ (2020). Target protection as a key antibiotic resistance mechanism. Nature Reviews Microbiology, 18: 637-648
• IV. Kime L, Randall CP, Banda FI, Coll F, Wright J, Richardson J, Empel J, Parkhill J, O'Neill AJ. 2019. Transient Silencing of Antibiotic Resistance by Mutation Represents a Significant Potential Source of Unanticipated Therapeutic Failure. mBio, 10: e01755-19
  

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