In vitro antifungal and antibiofilm activities of auranofin against itraconazole-resistant Aspergillus fumigatus

IF 2.2 4区医学 Q3 MYCOLOGY

Journal de mycologie medicale Pub Date : 2023-05-01 DOI:10.1016/j.mycmed.2023.101381

Peiying Chen , Jing Yang , Yuanling Jin , Chujie Lu , Zhenzhen Feng , Fei Gao , Yuan Chen , Fuling Wang , Zhuo Shang , Wei Lin

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引用次数: 0

Abstract

Background

Infections caused by azole-resistant Aspergillus are a rising public health threat with high mortality rates, high treatment costs and limited available antifungals, indicating an urgent need for new antifungals or strategies. Our aim was to investigate antifungal and antibiofilm activities of auranofin, an FDA-approved anti-antirheumatic drug.

Methods

Fungal susceptibility testing for auranofin was carried out by the broth-based microdilution methods. Cell viability treated by auranofin was tested by resazurin dye testing. The synergistic effect of auranofin and antifungal drugs was evaluated using checkboard assay. The inhibitory of biofilms were measured by crystal violet staining. Gene expression level analysis and enzyme activity was investigated with qRT-PCR analysis and DTNB assay. The key amino acid residues in the binding of auranofin with A. fumigatus thioredoxin reductase (AfTrxR) were indicated by structural analyses, site-directed mutagenesis, and microscale thermophoresis (MST) assays.

Results

Auranofin has fungicidal activity and in vitro antifungal spectrum including Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus, Aspergillus niger, even itraconazole (ITC)-resistant A. fumigatus. Additionally, it has antibiofilm activities against ITC-resistant A. fumigatus by reducing the expression level of SomA and MedA. Moreover, we discovered a synergistic effect of auranofin and ITC or amphotericin B against ITC-resistant A. fumigatus. Auranofin downregulated the gene transcription of AfTrxR, and strongly inhibited the enzyme activity of AfTrxR through interacting with residues C145 and C148.

Conclusions

Auranofin has fungicidal and antibiofilm activities in Aspergillus spp. and is also a potentiator of ITC or amphotericin B in vitro.

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金糠蛋白对耐伊曲康唑烟曲霉的体外抑菌及抗菌活性研究

背景抗唑曲霉菌引起的感染是一种日益严重的公共卫生威胁，死亡率高，治疗成本高，可用的抗真菌药物有限，这表明迫切需要新的抗真菌药或策略。我们的目的是研究金诺芬的抗真菌和抗生物膜活性，金诺芬是美国食品药品监督管理局批准的抗风湿病药物。方法采用肉汤微量稀释法对金诺芬进行真菌药敏试验。通过重氮祖林染色测试金诺芬处理的细胞活力。采用棋盘格法评价金诺芬与抗真菌药物的协同作用。通过结晶紫染色测定生物膜的抑制作用。用qRT-PCR分析和DTNB分析研究基因表达水平分析和酶活性。通过结构分析、定点诱变和微尺度热泳（MST）分析，确定了金诺芬与烟曲霉硫氧还蛋白还原酶（AfTrxR）结合的关键氨基酸残基。结果Auranofin具有杀菌活性和体外抗真菌谱，包括黄曲霉、烟曲霉、土曲霉、黑曲霉，甚至伊曲康唑（ITC）抗性烟曲霉。此外，它通过降低SomA和MedA的表达水平，对耐ITC的烟曲霉具有抗生物膜活性。此外，我们发现了金诺芬和ITC或两性霉素B对耐ITC烟曲霉的协同作用。Auranofin下调了AfTrxR的基因转录，并通过与残基C145和C148的相互作用强烈抑制了AfTrxR的酶活性。

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来源期刊

Journal de mycologie medicale 医学-真菌学

CiteScore

5.10

自引率

2.80%

发文量

审稿时长

6-12 weeks

期刊介绍： The Journal de Mycologie Medicale / Journal of Medical Mycology (JMM) publishes in English works dealing with human and animal mycology. The subjects treated are focused in particular on clinical, diagnostic, epidemiological, immunological, medical, pathological, preventive or therapeutic aspects of mycoses. Also covered are basic aspects linked primarily with morphology (electronic and photonic microscopy), physiology, biochemistry, cellular and molecular biology, immunochemistry, genetics, taxonomy or phylogeny of pathogenic or opportunistic fungi and actinomycetes in humans or animals. Studies of natural products showing inhibitory activity against pathogenic fungi cannot be considered without chemical characterization and identification of the compounds responsible for the inhibitory activity. JMM publishes (guest) editorials, original articles, reviews (and minireviews), case reports, technical notes, letters to the editor and information. Only clinical cases with real originality (new species, new clinical present action, new geographical localization, etc.), and fully documented (identification methods, results, etc.), will be considered. Under no circumstances does the journal guarantee publication before the editorial board makes its final decision. The journal is indexed in the main international databases and is accessible worldwide through the ScienceDirect and ClinicalKey platforms.