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Expanding antibiotic chemical space through precursor-directed biosynthesis

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thesis
posted on 28.03.2022, 18:57 by Mahmud Tareq Morshed
The rapid emergence of multidrug-resistant microorganisms demands continuous development of new antibiotics with novel modes of action. However, very few candidates are currently in the pipeline. The present study addresses this challenge by combining natural product chemistry, precursor-directed biosynthesis and chemical derivatisation to expand the chemical space around nidulin, an antibiotic depsidone first isolated from Aspergillus nidulans in 1944. Initial optimisation of culture media led to two new fungal metabolites, 7-carboxyfolipastatin and unguinolic acid, as well as four previously reported compounds. In precursor-directed biosynthesis experiments, Aspergillus unguis was fed unnatural salicylic acid and orsellinic acid derivatives, which did not yield any new nidulin analogues. However, supplementing the culture medium with halide salts led to three new depsides, unguidepside A, unguidepside B and 5-bromoagonodepside B, and one new depsidone, 2-bromo-7-chlorounguinol. Finally, a semi-synthetic approach was employed to generate six nidulin analogues. All natural, unnatural and semi-synthetic compounds were screened for antibacterial, antifungal and cell cytotoxicity activities. Among the new depsides and depsidones, 2-bromo-7-chlorounguinol showed good antibacterial activity (IC50 2.8 μg/mL), while 2,4-diiodo-1ʹ,2ʹ-dihydrounguinol exhibited the highest antibacterial activity (IC50 0.99 μg/mL) against Bacillus subtilis among the all synthetic compounds. A structure-activity relationship for the nidulin pharmacophore was proposed.

History

Table of Contents

1. Introduction -- 2. Optimisation of cultivation conditions for Aspergillus unguis -- 3. Precursor-directed biosynthesis of nidulin analogues -- 4. Semi-synthesis of nidulin analogues -- 5. Bioassay and SAR -- 6. Experimental -- 7. References -- 8. Supplementary material.

Notes

Bibliography: pages 51-57 Empirical thesis.

Awarding Institution

Macquarie University

Degree Type

Thesis MRes

Degree

MRes, Macquarie University, Faculty of Science and Engineering, Department of Chemistry and Biomolecular Sciences

Department, Centre or School

Department of Chemistry and Biomolecular Sciences

Year of Award

2016

Principal Supervisor

Andrew Michael Piggott

Additional Supervisor 1

Peter Karuso

Rights

Copyright Mahmud Tareq Morshed 2016. Copyright disclaimer: http://mq.edu.au/library/copyright

Language

English

Extent

1 online resource (vi, 68 pages) diagrams, graphs, tables

Former Identifiers

mq:69631 http://hdl.handle.net/1959.14/1256265