Studies towards high performance multivalent ligands for negatively charged membranes and photophysical characterization of bacterial cell membrane targeting photodynamic inactivation agents

Date

2023-7-20

Author

Akbulut, Doğan

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The discovery and widespread clinical use of antibiotics has been one of the most important developments in medicine. The widespread, and frequently unnecessary, use of antibiotics has resulted in the frequent and continuous emergence of bacterial strains resistant to antibiotics in clinical use. As a result, pathogenic bacterial strains exist now that do not respond to any known antibiotics. Antibiotic resistant bacteria are one of the most important risks to public health. There are several approaches that could be taken to tackle this problem. One approach is to enhance the selectivity of antibiotic agents by conjugating them with bacterial targeting groups to widen their therapeutic window. Antibodies, peptides, modified antibiotics, polycationic compounds, carbohydrates, and certain metal complexes are among bacterial targeting groups that may be used for this purpose. In this context zinc(II) bisdipcolylamine (Zn2BDPA) complexes have been developed as highly selective ligands for the negatively charged membranes of bacterial cells. While these complexes are very valuable, there is a need to improve their binding affinities towards bacterial membranes. The aim of the work summarized in this thesis is two-fold: The first objective was to exploit the concept of multivalency to enhance the affinity of Zn2BDPA complexes towards bacterial cell membranes. Multiple copies of Zn2BDPA and ZnDPA complexes were covalently attached to certain scaffolds such as cholic acid and derivatives and the affinity of such systems towards negatively charged membranes will be determined using indicator displacement assays in future studies. Also in future studies, conjugates of such high performance multivalent ligands with dyes will be prepared as effective optical imaging agents for bacterial cells. Zn2BDPA and ZnDPA complexes were also attached to another steroidal structure, namely cholesterol, to be components in liposomal systems to be used as bacterial agglutination agents. The selectivity of Zn2BDPA conjugated cholesterol bearing liposomes towards negatively charged biomembranes was shown through liposomal and bacterial agglutination studies. The second objective was to investigate the photophysical properties of a number of Zn2BDPA-porphyrin derivatives which were prepared as potential antibacterial photodynamic therapy (aPDT) agents. Relative singlet and fluorescence quantum yields of these derivatives in CHCl3 were calculated investigate the potential of these derivatives as aPDT agents.

Subject Keywords

Bisdipicolylamine ligands, Antibiotic resistance, Multivalency, Bacteria, Porphyrins

URI

https://hdl.handle.net/11511/104873

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Graduate School of Natural and Applied Sciences, Thesis