The aquastatin biosynthetic gene cluster encodes a versatile polyketide synthase capable of synthesising heteromeric depsides with diverse alkyl side chains

被引：2

作者：

Sbaraini, Nicolau ^{[1
]}

Crombie, Andrew ^{[2
]}

Kalaitzis, John A. ^{[3
]}

Vuong, Daniel ^{[2
]}

Bracegirdle, Joe ^{[1
,2
]}

Windsor, Fraser ^{[1
]}

Lau, Ashli ^{[1
]}

Chen, Rachel ^{[2
]}

Tan, Yu Pei ^{[4
,5
]}

Lacey, Alastair ^{[2
]}

Lacey, Ernest ^{[2
,3
]}

Piggott, Andrew M. ^{[3
]}

Chooi, Yit-Heng ^{[1
]}

机构：

[1] Univ Western Australia, Sch Mol Sci, Perth, WA 6009, Australia

[2] Microbial Screening Technol Pty Ltd, Smithfield, NSW 2164, Australia

[3] Macquarie Univ, Sch Nat Sci, Sydney, NSW 2109, Australia

[4] Plant Pathol Herbarium, Dept Agr & Fisheries, Dutton Pk, Qld 4102, Australia

[5] Univ Southern Queensland, Ctr Crop Hlth, Toowoomba, Qld 4350, Australia

来源：

CHEMICAL SCIENCE | 2024年 / 15卷 / 45期

基金：

澳大利亚研究理事会;

关键词：

ACID; IDENTIFICATION; BACTERIAL;

D O I：

10.1039/d4sc05557h

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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 Delta 15,16 and Delta 18,19 double bonds, which have superior bioactivities compared to the aquastatins but are only present as minor compounds in the native fungus A. gemini.

引用

页码：18872 / 18880

页数：9