Thesis
Investigating altered metabolism as a potential therapeutic target in antimicrobial resistance
- Abstract:
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Antimicrobial resistance poses a critical threat to global health, demanding innovative approaches to mitigate its impact. This study investigates metabolic adaptations underlying antibiotic resistance, focusing on the New Delhi metallo-β-lactamase enzyme, which hydrolyses carbapenems and confers high-level resistance. The primary objective was to identify metabolic vulnerabilities in resistant Escherichia coli strains that could be exploited as therapeutic targets to mitigate resistance. By characterising strain-specific metabolic changes under both basal and meropenem exposure, this study aims to inform the development of combination therapies pairing antibiotics with metabolic inhibitors.
Using genetically engineered bacterial strains – wild-type, meropenem-susceptible, and meropenem-resistant – untargeted metabolomics was performed, employing an optimised anion exchange chromatography-mass spectrometry method. Comprehensive analysis revealed significant metabolic reprogramming associated with plasmid carriage and New Delhi metallo-β-lactamase-7 gene expression. Key pathways impacted included nucleotide metabolism, central carbon metabolism, and amino acid biosynthesis, highlighting critical differences between resistant and non-resistant strains.
These findings demonstrate that metabolic changes associated with resistance impose unique vulnerabilities in resistant strains, presenting promising target for disruption. This work highlights the utility of metabolomics in uncovering strain-specific metabolic dependencies, advancing efforts to combat antimicrobial resistance through innovative therapeutic strategies that enhance antibiotic efficacy.
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(Preview, Dissemination version, pdf, 28.1MB, Terms of use)
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Authors
Contributors
+ Calvopina Tapia, K
- Institution:
- University of Oxford
- Division:
- MPLS
- Department:
- Chemistry
- Sub department:
- Organic Chemistry
- Role:
- Contributor
+ Walsby-tickle, J
- Institution:
- University of Oxford
- Division:
- MPLS
- Department:
- Chemistry
- Sub department:
- Chemical Biology
- Role:
- Contributor
- ORCID:
- 0000-0002-1287-9580
+ McCullagh, J
- Institution:
- University of Oxford
- Division:
- MPLS
- Department:
- Chemistry
- Sub department:
- Chemical Biology
- Role:
- Supervisor
- ORCID:
- 0000-0003-4733-1205
+ Schofield, C
- Institution:
- University of Oxford
- Division:
- MPLS
- Department:
- Chemistry
- Sub department:
- Organic Chemistry
- Role:
- Examiner
- ORCID:
- 0000-0002-0290-6565
- DOI:
- Type of award:
- DPhil
- Level of award:
- Doctoral
- Awarding institution:
- University of Oxford
- Language:
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English
- Keywords:
- Subjects:
- Deposit date:
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2026-04-28
- ARK identifier:
Terms of use
- Copyright holder:
- Kyoung Eun Lee
- Copyright date:
- 2025
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