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Abstract
Depsides have garnered substantial interest due to the diverse biological activities exhibited by members of this class. Among these are the antibacterial aquastatins, glycosylated heteromeric depsides formed through the condensation of orsellinic acid with corticiolic acid. In this work, we isolated aquastatins and the recently described geministatins, along with several novel aquastatin-related depsides with different alkyl side chains from the fungus Austroacremonium gemini MST-FP2131. The structures were determined through comprehensive spectroscopic analysis and chemical degradation. Genome mining and heterologous expression in Aspergillus nidulans and Saccharomyces cerevisiae revealed that aquastatin biosynthesis requires only two genes: a non-reducing polyketide synthase (SAT-KS-AT-PT-ACP-TE) and a glycosyltransferase. We demonstrated that the single polyketide synthase can synthesise an acetyl-primed orsellinic acid and alkylresorcylate with various chain lengths (C14, C16, or C18) by incorporating different long-chain acyl-CoAs as starter units, and then join these as heteromeric depsides. Using chemical degradation, we generated a series of analogues and showed that several aglycone depsides exhibit antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA), as well as antifungal and cytotoxic activities. Interestingly, heterologous expression of the aquastatin gene cluster in A. nidulans produced higher levels of geministatins with Δ15,16 and Δ18,19 double bonds, which have superior bioactivities compared to the aquastatins but are only present as minor compounds in the native fungus A. gemini.
Original language | English |
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Pages (from-to) | 18872-18880 |
Number of pages | 9 |
Journal | Chemical Science |
Volume | 15 |
Issue number | 45 |
Early online date | 24 Oct 2024 |
DOIs | |
Publication status | Published - 24 Oct 2024 |
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Unleashing the Hidden Chemical Diversity in Australian Fungi
Chooi, H. (Investigator 01), Piggott, A. (Investigator 02) & Lacey, E. (Investigator 03)
ARC Australian Research Council
11/05/22 → 10/05/25
Project: Research
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High Throughput NMR Facility
Koutsantonis, G. (Investigator 01), Kilburn, M. (Investigator 02), Swaminatha Iyer, I. (Investigator 03), Low, P. (Investigator 04), Broadhurst, D. (Investigator 05), Grierson, P. (Investigator 06), Massi, M. (Investigator 07) & Ogden, M. (Investigator 08)
ARC Australian Research Council , Curtin University, Edith Cowan University, Murdoch University
1/01/19 → 11/04/20
Project: Research
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Uncovering the Hidden Secondary Metabolite Biosynthetic Potential of Fungi
Chooi, H. (Investigator 01)
ARC Australian Research Council
1/01/17 → 15/03/21
Project: Research