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The synthesis and evaluation of novel soluble lytic transglycosylase inhibitors

Mezoughi, Aysha 2019. The synthesis and evaluation of novel soluble lytic transglycosylase inhibitors. PhD Thesis, Cardiff University.
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Lytic transglycosylases (LTs) present an attractive target of antibiotics due to their unique function in bacterial cell growth and division. They act on peptidoglycan (PG) by creating spaces via non-hydrolytic reactions to facilitate insertion of cell-envelop spanning structures that the cell requires for PG biosynthesis and recycling. In addition to that, these enzymes are involved in pivotal cell events including control of -lactamases expression (enzymes that confer resistance to -lactam antibiotics) by formation of the 1,6-anhydromuramic acid product. The most common compound used to inhibit LTs is Bulgecin. In this study, sixteen novel dihydroxylated amidine inhibitors were derived from 2-deoxy-D-ribose (eight free bases and eight hydrochloride salts) and four free bases were synthesised starting from 2-deoxy-L-ribose. Molecular docking was performed on the first five designed amidines from 2-deoxy-D-ribose and their analogues from 2-deoxy-L-ribose. The synthetic route employed involved sugar oxidation and azide reduction followed by ring opening and closure and transformation of lactam to amidine as key steps. However, a number of difficulties were faced this synthetic route in some reactions and purification. Synthesis of trihydroxylated amidines failed in the conversion step of lactam to thiolactam. In order to evaluate the synthesised inhibitors, membrane-bound soluble lytic transglycosylase (Slt35) was expressed, purified and its activity was optimised. The amidines were tested their activity against Slt35 revealing that most compounds derived from 2-deoxy-D-ribose exhibited inhibition toward Slt35 activity at high micromolar level whereas analogues derived from 2-deoxy-L-ribose were all inactive except one. In general, free base amidines are more potent than hydrochloride salts. Crystallisation of the best inhibitor generated in this study with Slt35 would be useful to investigate its interactions and improve its potency as antibacterial agent as well as testing the activity of all active compounds against bacteria.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Chemistry
Subjects: Q Science > QD Chemistry
Date of First Compliant Deposit: 20 September 2019
Last Modified: 29 Mar 2021 12:44

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