铁螯合土霉素A-C的生物合成及其在土曲霉感染中的作用-动脉网

Biosynthesis of iron-chelating terramides A-C and their role in Aspergillus terreus infection

Nature 等信源发布 2024-09-30 14:09

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AbstractFungal natural products from various species often feature hydroxamic acid motifs that have the ability to chelate iron. These compounds have an array of medicinally and ecologically relevant activities. Through genome mining, gene deletion in the host Aspergillus terreus, and heterologous expression experiments, this study has revealed that a nonribosomal peptide synthetase (NRPS) TamA and a specialized cytochrome P450 monooxygenase TamB catalyze the sequential biosynthetic reactions in the formation of terramides A-C, a series of diketopiperazines (DKPs) with hydroxamic acid motifs.

摘要来自各种物种的真菌天然产物通常具有异羟肟酸基序，具有螯合铁的能力。这些化合物具有一系列与医学和生态相关的活性。。

Feeding experiments showed that TamB catalyzes an unprecedented di-hydroxylation of the amide nitrogens in the diketopiperazine core. This tailoring reaction led to the formation of two bidentate iron-binding sites per molecule with an unusual iron-binding stoichiometry. The structure of the terramide A-Fe complex was characterized by liquid chromatography-mass spectrometry (LC-MS), Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy and electron paramagnetic resonance spectroscopy (EPR).

喂食实验表明，TamB催化二酮哌嗪核心中酰胺氮的前所未有的二羟基化。这种定制反应导致每个分子形成两个双齿铁结合位点，具有不寻常的铁结合化学计量。通过液相色谱-质谱（LC-MS），傅立叶变换红外光谱（FT-IR），拉曼光谱和电子顺磁共振光谱（EPR）表征了terramide A-Fe复合物的结构。

Antimicrobial assays showed that the iron-binding motifs are crucial for the activity against bacteria and fungi. Murine infection experiments indicated that terramide production is crucial for the virulence of A. terreus and could be a potential antifungal drug target..

抗菌试验表明，铁结合基序对于抗细菌和真菌的活性至关重要。小鼠感染实验表明，土拉酰胺的产生对A.terreus的毒力至关重要，可能是潜在的抗真菌药物靶标。。

IntroductionIron is one of the essential elements for life system, but its low solubility limits the uptake and utilization by organisms1. Microorganisms growing under iron-limiting conditions will synthesize low molecular-weight iron chelators. Most of these molecules are produced by nonribosomal peptide synthetases (NRPSs) or NRPS-independent (NIS), and they can be further classified into different groups: catecolates, carboxylates, hydroxamates, and mixed types2.

引言铁是生命系统的必需元素之一，但其低溶解度限制了生物体的吸收和利用1。在铁限制条件下生长的微生物将合成低分子量铁螯合剂。这些分子中的大多数是由非核糖体肽合成酶（NRPS）或不依赖NRPS（NIS）产生的，它们可以进一步分为不同的组：儿茶酸酯，羧酸盐，异羟肟酸酯和混合型2。

Hydroxamic acids are a class of weakly acidic compounds that can form stable chelates with a variety of transition metals3. Fungi mainly synthesize hydroxamic acid siderophores, which have great chelating ability to Fe(III). They can be divided into monohydroxamic acid, such as aspergillic acid, bishydroxamic acids, such as mycelianamide, schizokinen, terregens factor, rhodotorulic acid, mycobactins P and T, and trihydroxamic acids, such as ferrichrome, coprogen, fusarinine C and ferrioxamine4.

异羟肟酸是一类弱酸性化合物，可以与多种过渡金属形成稳定的螯合物3。真菌主要合成异羟肟酸铁载体，对Fe（III）具有很强的螯合能力。它们可以分为单异羟肟酸，如曲霉菌酸，双异羟肟酸，如菌丝体酰胺，裂殖因子，terregens因子，红酵母酸，分枝杆菌素P和T，以及三异羟肟酸，如铁色素，coprogen，镰刀菌素C和铁氧胺4。

Due to their iron-chelating ability, siderophores are produced by various pathogenic microorganisms as virulence factors during host infection to acquire essential iron from the host5. For example, the iron uptake system of Aspergillus fumigatus has been well characterized and shown to be indispensable for fungal infection6.

由于它们的铁螯合能力，各种病原微生物在宿主感染期间产生铁载体作为毒力因子，以从宿主获得必需铁5。。

While the production of siderophores is a hallmark of pathogenicity, these compounds can also be repurposed for beneficial applications, including targeted antibiotic delivery, cancer treatment, vaccine development, and diagnostics7,8,9,10,11.Siderophores can be connected to antibiotic molecules through a molecular linker.

虽然铁载体的产生是致病性的标志，但这些化合物也可以用于有益的应用，包括靶向抗生素递送，癌症治疗，疫苗开发和诊断7,8,9,10,11。铁载体可以通过分子接头连接到抗生素分子。

The siderophore part will be recognized and actively taken up into the cell where the antibiotic part of the conjugate can kill the pathogen12. In addition, deferoxamine B is us.

铁载体部分将被识别并主动吸收到细胞中，其中缀合物的抗生素部分可以杀死病原体12。此外，去铁胺B是美国的。

Data availability

数据可用性

The authors declare that all data supporting the findings of this study are available within the paper and its supplementary information and supplementary data files. Supplementary Data 1: Figures original data. Supplementary Data 2: The cif files of compounds 1 and 2. The X-ray crystallographic coordinates for structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers CCDC 2340113, 2380314.

作者声明，支持本研究结果的所有数据均可在论文及其补充信息和补充数据文件中找到。补充数据1：数字原始数据。补充数据2：化合物1和2的cif文件。本文报道的结构的X射线晶体学坐标已保存在剑桥晶体学数据中心（CCDC），沉积编号为CCDC 23401132830314。

These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Supplementary Data 3: NMR spectra..

这些数据可以通过www.ccdc.cam.ac.uk/data\u request/cif从剑桥晶体学数据中心免费获得。补充数据3:NMR光谱。。

Code availability

代码可用性

The code used for the simulations is available from the authors upon request.

作者可根据要求提供用于模拟的代码。

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Xiong, Z. et al. Urease of Aspergillus fumigatus is required for survival in macrophages and virulence. Microbiol. Spectr. 11, e0350822 (2023).Download referencesAcknowledgementsY.G. discloses support for the research of this work from the International Postdoctoral Exchange Fellowship Program (Talent-Introduction Program) of the Office of China Postdoc Council (OCPC) (grant number.

熊，Z。等人。烟曲霉的脲酶是巨噬细胞存活和毒力所必需的。微生物。光谱。11，e0350822（2023）。下载referencesAcknowledgementsY。G、披露了中国博士后理事会（OCPC）办公室国际博士后交流奖学金计划（人才引进计划）对这项工作的研究支持（批准号）。

YJ20210168) and the Zhejiang Provincial Postdoctoral Research Project (grant number ZJ2022084). We thank Professor Yi Tang (UCLA) and Professor Berl R. Oakley (University of Kansas) for providing the A. nidulans expression system. We acknowledge Yanwei Li from the Core Facilities, Zhejiang University School of Medicine, for technical support.

YJ20210168）和浙江省博士后研究项目（批准号ZJ2022084）。我们感谢Yi Tang教授（加州大学洛杉矶分校）和Berl R.Oakley教授（堪萨斯大学）提供了构巢曲霉表达系统。我们感谢浙江大学医学院核心设施的李燕伟提供的技术支持。

Jianyang Pan from Research and Service Center, College of Pharmaceutical Sciences, Zhejiang University for NMR analysis, Dan Wu from Research and Service Center, College of Pharmaceutical Sciences, Zhejiang University for help with HR-ESI-MS, Jiyong Liu from Chemical Analysis Center, College of Chemistry, Zhejiang University for help with crystal structure determination.

。

Lijuan Mao from the Analysis Center of Agrobiology and Environmental Sciences, Zhejiang University, for help with FT-IR analysis. Chen Chen from the Chemical Experimental Teaching Demonstration Center, College of Chemistry, Zhejiang University, for help with Raman spectroscopy analysis. Xinyu Wang from Chemical Analysis Center, College of Chemistry, Zhejiang University, for help with EPR analysis.Author informationAuthor notesThese authors contributed equally: Yi Han, Yaojie Guo.Authors and AffiliationsDepartment of Microbiology, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, ChinaYi Han, Yaojie Guo, Nan Zhang, Fan Xu, Jarukitt Limwac.

浙江大学农业生物学与环境科学分析中心的毛丽娟（LijuanMao）为FT-IR分析提供了帮助。来自浙江大学化学学院化学实验教学示范中心的陈晨（Chen Chen）帮助进行拉曼光谱分析。浙江大学化学学院化学分析中心的王新宇（Xinyu Wang）帮助进行EPR分析。作者信息作者注意到这些作者做出了同样的贡献：Yi Han，Yaojie Guo。作者和附属机构浙江大学医学院基础医学院微生物学系，杭州，中国汉族，郭耀杰，张南，范旭，Jarukitt-Limwac。

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PubMed Google ScholarContributionsYi Han, Yaojie Guo: Investigation, Conceptualization, Formal analysis, Investigation, Data provision and curation, Writing-original draft, Writing-review & editing, Funding acquisition. Nan Zhang: Investigation, Data provision. Fan Xu: Investigation.

PubMed谷歌学术贡献Yi Han，Yaojie Guo：调查，概念化，形式分析，调查，数据提供和管理，撰写原稿，撰写评论和编辑，资金获取。张楠：调查，数据提供。范旭：调查。

Jarukitt Limwachiranon: Funding acquisition. Zhenzhen Xiong: Validation. Liru Xu: Investigation. Xu-Ming Mao: Resources. Daniel H. Scharf: Conceptualization, Supervision, Project administration, Funding acquisition, Writing-review & editing. Yi Han and Yaojie Guo contributed equally to this work. All authors have given approval to the final version of the manuscript.Corresponding authorCorrespondence to.

Jarukitt Limwachiranon：资金收购。熊振珍：验证。徐丽茹：调查。徐明茂：资源。Daniel H.Scharf：概念化，监督，项目管理，资金获取，写作评论和编辑。易汉和郭耀杰对这项工作做出了同样的贡献。所有作者都同意稿件的最终版本。对应作者对应。

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Reprints and permissionsAbout this articleCite this articleHan, Y., Guo, Y., Zhang, N. et al. Biosynthesis of iron-chelating terramides A-C and their role in Aspergillus terreus infection.

转载和许可本文引用本文Han，Y.，Guo，Y.，Zhang，N。等人。铁螯合土酰胺A-C的生物合成及其在土曲霉感染中的作用。

Commun Chem 7, 221 (2024). https://doi.org/10.1038/s42004-024-01311-2Download citationReceived: 04 July 2024Accepted: 17 September 2024Published: 30 September 2024DOI: https://doi.org/10.1038/s42004-024-01311-2Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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