山奈酚作为新型ADAM10抑制剂治疗金黄色葡萄球菌感染

王婷婷, 王建锋, 许湘竹, 蒋帆, 吕红发, 齐清辉, 张灿, 吕强华, 邓旭明

工程（英文） ›› 2023, Vol. 28 ›› Issue (9) : 206-221.

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工程（英文） ›› 2023, Vol. 28 ›› Issue (9) : 206-221. DOI: 10.1016/j.eng.2023.03.006
研究论文
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山奈酚作为新型ADAM10抑制剂治疗金黄色葡萄球菌感染

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Discovery of Kaempferol, a Novel ADAM10 Inhibitor, as a Potential Treatment for Staphylococcus aureus Infection

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摘要

宿主靶向疗法（HDT）是近年来兴起一种的治疗多重耐药金黄色葡萄球菌（S. aureus，简称“金葡菌”）感染的新策略。去整合素和金属蛋白酶10（ADAM10）作为α-毒素（Hla）不可或缺的特异性细胞受体，可通过多种机制促进金葡菌感染。ADAM10在致病机制中发挥的关键作用使其成为基于HDT治疗金葡菌感染的有力靶点。本研究首次证明ADAM10在金葡菌诱导的坏死性调亡中也发挥重要作用，这一发现拓宽了人们对ADAM10在金葡菌感染中作用的认识。通过荧光底物分解试验，我们进一步筛选出了一种强效ADAM10抑制剂——山奈酚，该化合物可抑制Hla引起的屏障破坏和细胞坏死性调亡，有效保护小鼠免受金葡菌感染。总的来说，本研究提出了一种新的宿主靶向治疗策略，并提供了有较高应用前景的候选化合物山奈酚。

Abstract

Host-directed therapy (HDT) is an emerging novel approach for treating multidrug-resistant Staphylococcus aureus (S. aureus) infection. Functioning as the indispensable specific cellular receptor for α-toxin (Hla), a-disintegrin and metalloproteinase 10 (ADAM10) is exploited to accelerate S. aureus infection through diverse mechanisms. The extraordinary contribution of ADAM10 to S. aureus pathogenesis renders it an attractive HDT target for combating S. aureus infection. Our study is the first to demonstrate the indispensable role of ADAM10 in S. aureus-induced necroptosis, and it enhances our knowledge of the role of ADAM10 in S. aureus infection. Using a fluorogenic substrate assay, we further identified kaempferol as a potent ADAM10 inhibitor that effectively protected mice from S. aureus infection by suppressing Hla-mediated barrier disruption and necroptosis. Collectively, our work presents a novel host-directed therapeutic strategy for using the promising candidate kaempferol to treat S. aureus infection and other diseases relevant to the disordered upregulation of ADAM10.

关键词

宿主靶向治疗 / 山奈酚 / ADAM10抑制剂 / 金黄色葡萄球菌感染 / 屏障破坏 / 坏死性调亡

Keywords

Host-directed therapy / Kaempferol / ADAM10 inhibitor / Staphylococcus aureus infection / Barrier disruption / Necroptosis

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王婷婷, 王建锋, 许湘竹. 山奈酚作为新型ADAM10抑制剂治疗金黄色葡萄球菌感染. Engineering. 2023, 28(9): 206-221 https://doi.org/10.1016/j.eng.2023.03.006

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