Investigating the antibiotic and metal binding properties of obafluorin

Davie, Melissa (2021) Investigating the antibiotic and metal binding properties of obafluorin. Masters thesis, University of East Anglia.

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Humans have utilised natural products (NPs) throughout history for a variety of different applicationsincludinginas pharmaceuticals; more than seventy percent of the antibiotics we use today are NPs or their derivatives. This project focusses onthe NP,obafluorin,a broad-spectrum antibiotic produced by the bacterium Pseudomonas fluorescens. Its structure consistsof a -lactone coredecorated with a catecholmoietyand a 4-nitrophenyl group. -lactones, although susceptible to hydrolysis and attack by -lactamase enzymes, are components of various structurally diverse NPs with valuable biological activities. The biosynthesis of obafluorinin P. fluorescenshas been characterised previously and itsmolecular targethas been identified as the threonyl-tRNA synthetase (ThrRS) enzyme. However, its mechanism of action remainselusive. Here, I report progress towards understanding the properties of obafluorin and their role in itsmechanism of action. I used a biochemical approach to unpick the role of chemical constituents of the structure of obafluorin. The catechol was found to be essential for both the bioactivityand ferric iron binding properties of obafluorin. Through characterisation of theobafluorin-iron complex, I have found that iron binding is responsible for protecting the -lactoneofobafluorin from hydrolytic breakdown, and this to be vital for bioactivity. Unfortunately, studieson elucidation of the interaction between obafluorin and ThrRSwere thwarted due to the reactivity of the compoundinvitro. However,this report details significant progress made to understand the propertiesandbioactivity ofthis previously disregarded antibiotic. These studies highlight the importance of further investigations into “old” antibiotics and demonstrate the potential of antibiotic-iron interactions. This could represent an underexplored area of antibiotic research which could hold great value in the fight against antimicrobial resistance.

Item Type: Thesis (Masters)
Faculty \ School: Faculty of Science > School of Chemistry
Depositing User: Jackie Webb
Date Deposited: 29 Apr 2022 10:13
Last Modified: 29 Apr 2022 10:13


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