Exploring Alternative Strategies in Antibiotic Discovery to Tackle Multidrug-Resistant Bacteria
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(Library staff access only.)
Date
2024
Authors
Wyllie, Jessica Anne
Editors
Advisors
Soares da Costa, Tatiana
Trott, Darren
Unsworth, Nathan (Defence Science and Technology Group)
Trott, Darren
Unsworth, Nathan (Defence Science and Technology Group)
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Thesis
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Abstract
Although most bacteria were once susceptible to antibiotics, our reliance on the current arsenal has led to significant misuse and overuse, contributing to the emergence of antibiotic-resistant bacteria. Unfortunately, we are now rapidly approaching a ‘post-antibiotic’ era, where infections once routinely treated with antibiotics are no longer treatable. In fact, infectious disease is the second leading cause of death worldwide, further highlighting the urgent need to develop new antibiotics. However, the rate at which resistance is emerging has surpassed the rate at which new antibiotics are entering the market. On top of this, the clinical shelf-life of these life-saving therapeutics is dwindling, with resistance reported to most agents within 2 to 3 years of their clinical introduction. Thus, it is critical that we explore diverse strategies to increase the number of therapeutics entering the clinical pipeline. This thesis focused on providing proof-of-concept for three distinct strategies to help tackle the antibiotic resistance crisis: re-engineering existing antibiotics, exploring novel metal complexes as antibiotics, and identifying inhibitors of novel antibiotic targets. The first approach centred on re-engineering our current arsenal of antibiotics. To do so, we exploited the dimerisation phenomenon of vancomycin to develop a series of novel vancomycin dimers linked through a shapeshifting bullvalene core. These dimers possessed improved potency against bacterial strains resistant to vancomycin, and the inclusion of the fluxional bullvalene core reduced the propensity for susceptible bacteria to develop resistance. These results demonstrate the potential of dimerising antibiotics, which could allow us to exploit the synergistic relationship of two pharmacophores. The second approach explored the potential of novel metal complexes as antibiotics to circumvent the systemic bias that only organic compounds can be successful antibiotics. Specifically, we examined a series of silver and gold N-heterocyclic carbene complexes for their antibacterial activity, with the silver compounds more potent against Gram-negative bacteria whilst the gold complexes were more potent against Gram-positive bacteria. Furthermore, these complexes demonstrated reduced propensity for resistance development, indicating that metal complexes may provide a durable solution to the antibiotic resistance crisis. The third approach focused on identifying inhibitors of underexplored antibiotic targets through virtual high throughput screening. To do so, we developed a virtual screening pipeline that resulted in the identification of several inhibitors of the biosynthesis pathway of UDP-N-acetylglucosamine, an essential building block of bacterial peptidoglycan. Specifically, we identified the first inhibitors of phosphoglucosamine mutase (GlmM) and the first dual-target inhibitors of GlmM and the bifunctional glucosasmine-1-phosphate acetyltransferase/N-acetylglucosamine-1-phosphate uridyltransferase (GlmU) enzyme, demonstrating the validity of our virtual screening pipeline. In summary, this thesis provides proof-of-concept that by employing non-traditional antibiotic discovery strategies, we may increase the number of therapeutics entering the antibiotic discovery pipeline and protect future generations from a ‘post-antibiotic’ era.
School/Discipline
School of Agriculture, Food and Wine
Dissertation Note
Thesis (Ph.D.) -- University of Adelaide, School of Agriculture, Food and Wine, 2024
Provenance
This thesis is currently under embargo and not available.