Expanding antibiotic chemical space through precursor-directed biosynthesis

Mahmud Morshed, Daniel Vuong, Andrew Crombie, Ernest Lacey, Andrew Piggott

Research output: Contribution to conferencePosterResearch

Abstract

Nidulin is a fungal depsidone antibiotic first isolated in 1944 from the fungus Aspergillus nidulans. Nidulin shows potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). In this study, we have employed a combination of natural products chemistry, precursor-directed biosynthesis and chemical derivatisation to expand chemical space around the nidulin pharmacophore. 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 supplemented with halide salts, leading 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 antitumour activities. Based on these bioassay results, a structure-activity relationship for the nidulin pharmacophore was proposed.

Conference

ConferenceThe Royal Australian Chemical Institute NSW Organic Chemistry Group Annual One-Day Symposium (37th : 2016)
CitySydney, Australia
Period30/11/1630/11/16

Fingerprint

Biosynthesis
Anti-Bacterial Agents
Aspergillus
Depsides
Methicillin
Bioassay
Metabolites
Biological Products
Fungi
Culture Media
Salts
nidulin
Acids
Experiments
depsidone

Cite this

Morshed, M., Vuong, D., Crombie, A., Lacey, E., & Piggott, A. (2016). Expanding antibiotic chemical space through precursor-directed biosynthesis. 56. Poster session presented at The Royal Australian Chemical Institute NSW Organic Chemistry Group Annual One-Day Symposium (37th : 2016), Sydney, Australia, .
Morshed, Mahmud ; Vuong, Daniel ; Crombie, Andrew ; Lacey, Ernest ; Piggott, Andrew. / Expanding antibiotic chemical space through precursor-directed biosynthesis. Poster session presented at The Royal Australian Chemical Institute NSW Organic Chemistry Group Annual One-Day Symposium (37th : 2016), Sydney, Australia, .1 p.
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Morshed, M, Vuong, D, Crombie, A, Lacey, E & Piggott, A 2016, 'Expanding antibiotic chemical space through precursor-directed biosynthesis' The Royal Australian Chemical Institute NSW Organic Chemistry Group Annual One-Day Symposium (37th : 2016), Sydney, Australia, 30/11/16 - 30/11/16, pp. 56.

Expanding antibiotic chemical space through precursor-directed biosynthesis. / Morshed, Mahmud; Vuong, Daniel; Crombie, Andrew; Lacey, Ernest; Piggott, Andrew.

2016. 56 Poster session presented at The Royal Australian Chemical Institute NSW Organic Chemistry Group Annual One-Day Symposium (37th : 2016), Sydney, Australia, .

Research output: Contribution to conferencePosterResearch

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T1 - Expanding antibiotic chemical space through precursor-directed biosynthesis

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AU - Vuong, Daniel

AU - Crombie, Andrew

AU - Lacey, Ernest

AU - Piggott, Andrew

PY - 2016/11/30

Y1 - 2016/11/30

N2 - Nidulin is a fungal depsidone antibiotic first isolated in 1944 from the fungus Aspergillus nidulans. Nidulin shows potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). In this study, we have employed a combination of natural products chemistry, precursor-directed biosynthesis and chemical derivatisation to expand chemical space around the nidulin pharmacophore. Initial optimisation of culture media led to two new fungal metabolites, 7-carboxyfolipastatin and unguinolic acid, as well as fourpreviously reported compounds. In precursor-directed biosynthesis experiments, Aspergillus unguis was supplemented with halide salts, leading 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 antitumour activities. Based on these bioassay results, a structure-activity relationship for the nidulin pharmacophore was proposed.

AB - Nidulin is a fungal depsidone antibiotic first isolated in 1944 from the fungus Aspergillus nidulans. Nidulin shows potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). In this study, we have employed a combination of natural products chemistry, precursor-directed biosynthesis and chemical derivatisation to expand chemical space around the nidulin pharmacophore. Initial optimisation of culture media led to two new fungal metabolites, 7-carboxyfolipastatin and unguinolic acid, as well as fourpreviously reported compounds. In precursor-directed biosynthesis experiments, Aspergillus unguis was supplemented with halide salts, leading 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 antitumour activities. Based on these bioassay results, a structure-activity relationship for the nidulin pharmacophore was proposed.

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Morshed M, Vuong D, Crombie A, Lacey E, Piggott A. Expanding antibiotic chemical space through precursor-directed biosynthesis. 2016. Poster session presented at The Royal Australian Chemical Institute NSW Organic Chemistry Group Annual One-Day Symposium (37th : 2016), Sydney, Australia, .