Year
2023
Degree Name
Doctor of Philosophy
Department
School of Chemistry and Molecular Bioscience
Abstract
Clostridioides difficile is fast becoming a worldwide healthcare concern due to high associated morbidity and mortality rates of hospital associated infections. Current front-line antibiotics used against C. difficile such as vancomycin and fidaxomicin have shown high rates of recovery, however no current antibiotic treatment is able to eliminate the spores of C. difficile which are commonly associated with relapse and recurrence of C. difficile infection (CDI). Previous work from our group has shown that cephamycin-type antibiotics, especially cefotetan, can directly bind to the active site of CdSpoVD — an essential protein for the production of spore cortex — and inhibit the sporulation activity of C. difficile. Thus, a collaborative project was established between UOW and Monash University, with the aim of designing novel cephamycin-type molecules that specifically target the sporulation process of C. difficile using cefotetan as the lead compound. Furthermore, the identification of the sporulation target CdSpoVD, and construction of CdSpoVD homology and AlphaFold (AF) models, enabled further development of structure-based drug design in aid of molecular docking studies.
Two synthetic pathways have been established for this project to functionalise the C-7 and the C-3 positions of a cephamycin-type compound, including a feasible method to install a methoxy group on the C-7 position of the molecule. The binding site of CdSpoVD was predicted by blind docking of the lead compound cefotetan with the homology model of CdSpoVD, which identified S311 as the catalytic serine residue. Five AF models of CdSpoVD were prepared by Prof. Haibo Yu, and the accuracies of these models were confirmed by the X-ray crystal structure of CdSpoVD when it was later reported. Methods for both non-covalent and covalent docking were developed and used for virtual screening of the cephamycin derivatives prior to their syntheses. The docking outcomes of synthesised compounds were also used in combination with their biological results to develop structure-activity relationship (SAR) data.
Recommended Citation
Cun, Wendy Yuhan, Design, Synthesis, and Evaluation of Cephamycin-based Anti-Sporulation Agents targeting Clostridioides difficile, Doctor of Philosophy thesis, School of Chemistry and Molecular Bioscience, University of Wollongong, 2023. https://ro.uow.edu.au/theses1/1719
FoR codes (2008)
0304 MEDICINAL AND BIOMOLECULAR CHEMISTRY, 0305 ORGANIC CHEMISTRY
Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.