Expanding antibiotic chemical space through precursor-directed biosynthesis

M. T. Morshed, D. Vuong, A. Crombie, E. Lacey, A. Piggott

Research output: Chapter in Book/Report/Conference proceedingConference proceeding contributionResearch

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 cell cytotoxicity activities. Based on these bioassay results, a structure-activity relationship for the nidulin pharmacophore was proposed.
LanguageEnglish
Title of host publicationRACI National Centenary Conference 2017
Subtitle of host publicationabstract book
Place of PublicationSydney
PublisherICMS Australasia
Pages507
Number of pages1
Publication statusPublished - 2017
EventRACI Centenary Congress - Melbourne Convention and Exhibition Centre, Melbourne, Australia
Duration: 23 Jul 201728 Jul 2017
http://www.racicongress.com

Conference

ConferenceRACI Centenary Congress
CountryAustralia
CityMelbourne
Period23/07/1728/07/17
Internet address

Fingerprint

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

Cite this

Morshed, M. T., Vuong, D., Crombie, A., Lacey, E., & Piggott, A. (2017). Expanding antibiotic chemical space through precursor-directed biosynthesis. In RACI National Centenary Conference 2017: abstract book (pp. 507). Sydney: ICMS Australasia.
Morshed, M. T. ; Vuong, D. ; Crombie, A. ; Lacey, E. ; Piggott, A. / Expanding antibiotic chemical space through precursor-directed biosynthesis. RACI National Centenary Conference 2017: abstract book. Sydney : ICMS Australasia, 2017. pp. 507
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Morshed, MT, Vuong, D, Crombie, A, Lacey, E & Piggott, A 2017, Expanding antibiotic chemical space through precursor-directed biosynthesis. in RACI National Centenary Conference 2017: abstract book. ICMS Australasia, Sydney, pp. 507, RACI Centenary Congress, Melbourne, Australia, 23/07/17.

Expanding antibiotic chemical space through precursor-directed biosynthesis. / Morshed, M. T.; Vuong, D.; Crombie, A.; Lacey, E.; Piggott, A.

RACI National Centenary Conference 2017: abstract book. Sydney : ICMS Australasia, 2017. p. 507.

Research output: Chapter in Book/Report/Conference proceedingConference proceeding contributionResearch

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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 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 cell cytotoxicity activities. Based on these bioassay results, a structure-activity relationship for the nidulin pharmacophore was proposed.

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Morshed MT, Vuong D, Crombie A, Lacey E, Piggott A. Expanding antibiotic chemical space through precursor-directed biosynthesis. In RACI National Centenary Conference 2017: abstract book. Sydney: ICMS Australasia. 2017. p. 507