Abstract
Antimicrobial resistance describes the ever-growing phenomenon whereby previously susceptible microorganisms gain resistance to, and do not respond to,rate of development of antibiotics, therapeutics crucial to modern healthcare, is not keeping up with resistance emergence, revealing demand for new antimicrobials. G quadruplex ligands hold potential as small molecule antibacterials that target intracellular G-quadruplex nucleic acid structures to dysregulate gene expression. In this dissertation, a panel of ligands including L9 (azobenzene), L5 (stiff-stilbene), NMA173 (diazocine), and the photo-switchable compounds LDD58-EZ (diazocine) and AR12 (diazocine) have been tested against clinically relevant bacterial species.
Antibacterial susceptibility tests (ASTs) were utilized to determine the spectrum of
activity of the ligands and revealed potent antibacterial activity against Gram-positive species, notably Staphylococcus aureus. With the exception of the azobenzene L9, activity against Gram-negative species was limited by target cell permeability Cytological and proteomic response profiling techniques of a permeabilised Escherichia coli strain were harnessed to gain detailed insight into specific cellular targets and mechanisms of bacterial killing. Bacterial cytological profiling (BCP) showed the ligands to have distinct modes of action (MoA), with analyses suggesting L9 and NMA173 to act as RNA transcription inhibitors. Proteomic responses of permeabilised E. coli challenged with the novel G-quadruplex ligands, alongside the previously characterized G-quadruplex ligand pyridostatin, were highly variable. The only commonality between all ligand-treated conditions was significant upregulation of the TorCAD operon, encoding proteins involved in trimethyl-amine N-oxide reduction in anaerobic respiration. LDD58-EZ was specifically identified as upregulating DNA damage associated proteins, pointing towards its potential as a nucleic acid effector.
Overall, the investigations described in this dissertation validate the potential for Gquadruplex ligands as novel antibacterial agents and justify their further investigation and optimisation.
| Date of Award | 20 Jan 2026 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Supervisor | Jim Spencer (Supervisor) & M C Galan (Supervisor) |
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