Expanding antibiotic chemical space around the nidulin pharmacophore

Mahmud T. Morshed, Daniel Vuong, Andrew Crombie, Alastair E. Lacey, Peter Karuso, Ernest Lacey, Andrew M. Piggott

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Reinvestigating antibiotic scaffolds that were identified during the Golden Age of antibiotic discovery, but have long since been "forgotten", has proven to be an effective strategy for delivering next-generation antibiotics capable of combatting multidrug-resistant superbugs. In this study, we have revisited the trichloro-substituted depsidone, nidulin, as a selective and unexploited antibiotic lead produced by the fungus Aspergillus unguis. Manipulation of halide ion concentration proved to be a powerful tool for modulating secondary metabolite production and triggering quiescent pathways in A. unguis. Supplementation of the culture media with chloride resulted in a shift in co-metabolite profile to dichlorounguinols and nornidulin at the expense of the non-chlorinated parent, unguinol. Surprisingly, only marginal enhancement of nidulin was observed, suggesting O-methylation may be rate-limiting. Similarly, supplementation of the media with bromide led to the production of the corresponding bromo-analogues, but also resulted in a novel family of depsides, the unguidepsides. Unexpectedly, depletion of chloride from the media halted the biosynthesis of the non-chlorinated parent compound, unguinol, and redirected biosynthesis to a novel family of ring-opened analogues, the unguinolic acids. Supplementation of the media with a range of unnatural salicylic acids failed to yield the corresponding nidulin analogues, suggesting the compounds may be biosynthesised by a single polyketide synthase. In total, 12 new and 11 previously reported nidulin analogues were isolated, characterised and assayed for in vitro activity against a panel of bacteria, fungi and mammalian cells, providing a comprehensive structure-activity profile for the nidulin scaffold.

LanguageEnglish
Pages3038-3051
Number of pages14
JournalOrganic and Biomolecular Chemistry
Volume16
Issue number16
DOIs
Publication statusPublished - 28 Apr 2018

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antibiotics
analogs
Anti-Bacterial Agents
biosynthesis
fungi
metabolites
Biosynthesis
Metabolites
Fungi
Scaffolds
chlorides
Chlorides
Depsides
Aspergillus
culture media
acids
methylation
Polyketide Synthases
profiles
ion concentration

Cite this

Morshed, Mahmud T. ; Vuong, Daniel ; Crombie, Andrew ; Lacey, Alastair E. ; Karuso, Peter ; Lacey, Ernest ; Piggott, Andrew M. / Expanding antibiotic chemical space around the nidulin pharmacophore. In: Organic and Biomolecular Chemistry. 2018 ; Vol. 16, No. 16. pp. 3038-3051.
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Expanding antibiotic chemical space around the nidulin pharmacophore. / Morshed, Mahmud T.; Vuong, Daniel; Crombie, Andrew; Lacey, Alastair E.; Karuso, Peter; Lacey, Ernest; Piggott, Andrew M.

In: Organic and Biomolecular Chemistry, Vol. 16, No. 16, 28.04.2018, p. 3038-3051.

Research output: Contribution to journalArticleResearchpeer-review

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