Chemical Probes to Investigate the Antibiotic Behaviour at the Molecular Level

This project aimed to design and synthesise a number of fluorescent chemical probes to develop a greater understanding the behaviour of antibiotic resistance, providing essential information that will be critical in the future research to prepare new antibacterial agents. In particular, the antibiotic interaction and function with peptidoglycan at the molecular level was called for special concern.

The work described in the thesis was mainly focused on the preparation of the fluorescent probes of thiazolidinone and quinazolinone and the synthesis of cyclic phosphonates which were supposed to show antibiotic activity. The small molecular transglycosylase inhibitor thiazolidinone showed good inhibitory effect against S. aureus with MIC of 16 ug/mL. The MIC of PBP inhibitor quinazolinone is 2 ug/mL against S. aureus. A series of chemical probes based on thiazolidinone and quinazolinone were successfully synthesised. However, the bioactivities of the prepared thiazolidinone and quinazolinone probes against S. aureus were limited and not qualified for labelling study, which required the development of new chemical probes. Cyclic phosphonates were supposed to inhibit nucleophilic serine and zinc-dependent β-lactamases as well as PBPs. Chemistry reactions were developed to prepare novel phosphonates, such as Kabachnik-Fields reaction, providing a great opportunity to discover new antibiotics.