Invasive and superficial infections caused by the Candida species result in significant global morbidity and mortality. As the pathogenicity of these organisms is intimately intertwined with host immune response, therapies to target both the fungus and host inflammation may be warranted. Structural similarities exist between established inhibitors of the NLRP3 inflammasome and those of fungal acetohydroxyacid synthase (AHAS). Therefore, we leveraged this information to conduct an in silico molecular docking screen to find novel polypharmacologic inhibitors of these targets that resulted in the identification of 12 candidate molecules. Of these, compound 10 significantly attenuated activation of the NLPR3 inflammasome by LPS + ATP, while also demonstrating growth inhibitory activity against C. albicans that was alleviated in the presence of exogenous branched chain amino acids, consistent with targeting of fungal AHAS. SAR studies delineated an essential molecular scaffold required for dual activity. Ultimately, 10 and its analog 10a resulted in IC₅₀ (IL-1β release) and MIC₅₀ (fungal growth) values with low μM potency against several Candida species. Collectively, this work demonstrates promising potential of dual-target approaches for improved management of fungal infections.

中文翻译：

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具有抗真菌和抗 NLRP3 炎症小体活性的双靶点化合物的鉴定

由念珠菌引起的侵袭性和浅表感染导致显着的全球发病率和死亡率。由于这些生物的致病性与宿主免疫反应密切相关，因此可能需要针对真菌和宿主炎症的治疗。已建立的 NLRP3 炎性体抑制剂与真菌乙酰羟酸合酶 (AHAS) 抑制剂之间存在结构相似性。因此，我们利用这些信息进行计算机分子对接筛选，以寻找这些靶点的新型多药抑制剂，从而鉴定出 12 个候选分子。其中，化合物10显着减弱了 LPS + ATP 对 NLPR3 炎性体的激活，同时还证明了对白色念珠菌的生长抑制活性，这种活性在存在外源支链氨基酸的情况下得到缓解，与真菌 AHAS 的靶向一致。SAR 研究描绘了双重活性所需的基本分子支架。最终，10及其类似物10a导致 IC ₅₀（IL-1β 释放）和 MIC ₅₀（真菌生长）值对几种念珠菌具有低 μM 效力。总的来说，这项工作展示了双靶点方法在改进真菌感染管理方面的巨大潜力。