- Title
- Biological characterisation of anthranilic acid holoenzyme assembly inhibitors
- Creator
- Miller, Michael
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2023
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- The antimicrobial resistance crisis is one of the greatest threats that humankind is facing in the 21st century. Comprehensive assessments of the global burden of antimicrobial resistance (AMR) estimate that 5 million deaths were associated with bacterial AMR in 2019. AMR is not a new problem, and for the first few decades of the antibiotic era, resistance was kept in check by developing and discovering new drugs. The lack of development of novel antibiotics has multiple overlapping causes that span the spheres of economics, policy, and science. Even with all efforts to reduce and reverse the AMR crisis, new antimicrobial drugs are still needed. A series of hybrid compounds incorporating anthranilic acid with activated 1H-indoles through a glyoxylamide linker were designed to target bacterial RNA polymerase holoenzyme formation. Biological testing of the hybrids identified a range of potent anti-transcription inhibitors with activity against a range of pathogenic bacteria with minimum inhibitory concentrations as low as 3.1 μM. A structure-activity relationship study identified the key structural components necessary to inhibit bacterial growth and transcription. Correlation of in vitro transcription inhibition activity with in vivo mechanism of action was established using fluorescence microscopy, and resistance passaging using Gram-positive bacteria showed no resistance development over 30 days. Furthermore, no toxicity was observed from the compounds in a wax moth larvae model, establishing a platform for the development of a series of new antibacterial drugs with an established mode of action. The compounds developed in this thesis are an excellent starting point for developing a series of potent new antimicrobial compounds. The future directions for this series of inhibitors are varied, but the resulting lead molecules would address underlooked clinical needs.
- Subject
- antibiotic; transcription; RNA Polymerase; biological
- Identifier
- http://hdl.handle.net/1959.13/1474494
- Identifier
- uon:49298
- Rights
- Copyright 2023 Michael Miller
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 6 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 1 MB | Adobe Acrobat PDF | View Details Download |