新型抑白念珠菌黄酮类化合物筛选、结构优化及作用机制研究

Screening, Structural Optimization and Mechanisms of Novel Flavonoid Compounds against Candida albicans

摘要: 白念珠菌是临床常见机会致病性真菌，可引起口腔、阴道、皮肤黏膜、导管相关感染及侵袭性血流感染。免疫抑制人群扩大、医用材料广泛应用以及唑类等抗真菌药物长期使用，使白念珠菌耐药、生物被膜相关感染和复发性感染问题日益突出。筛选具有新骨架、新作用方式和抗毒力活性的候选化合物，是抗白念珠菌药物研发的重要方向。黄酮类化合物来源广泛、结构类型丰富，兼具直接抑菌、抗毒力、抗生物被膜、氧化应激调节和药物增敏等活性，已成为新型抑白念珠菌先导化合物筛选与结构优化的重要资源。本文围绕异补骨脂查尔酮、黄芩素、槲皮素、黄芩苷、根皮素、柚皮苷、橙皮素、雌马酚、黄腐酚、异黄烷及查尔酮衍生物等代表性化合物，综述其筛选来源、抗白念珠菌活性、毒力因子和生物被膜干预效应、作用机制、结构优化线索及转化前景。现有研究表明，黄酮类化合物不仅可抑制浮游白念珠菌生长，还可干预黏附、酵母–菌丝转换、胞外水解酶和胞外多糖产生、生物被膜形成及成熟被膜发展；其机制涉及细胞膜/细胞壁损伤、麦角甾醇稳态破坏、活性氧过量生成、线粒体功能障碍、凋亡或自噬样死亡、cAMP-PKA信号调节、ENO1/烯醇化酶靶向、糖酵解抑制及外排泵功能干扰等。结构优化方面，查尔酮母核、α,β-不饱和羰基、邻位或多酚羟基、异戊烯基、杂环/卤素取代及适度疏水性与活性增强密切相关。未来研究应在标准化筛选和活性评价基础上，加强体内药效、安全性、直接靶点验证、联合用药和递药系统研究，以推动黄酮类抗真菌先导化合物向临床转化。

Abstract: Candida albicans is a common opportunistic fungal pathogen that can cause oral, vaginal, mucocutaneous, catheter-associated and invasive bloodstream infections. The expansion of immunosuppressed populations, widespread use of medical devices and prolonged application of azole antifungals have increased the clinical burden of drug resistance, biofilm-associated infection and recurrent disease. Screening candidate compounds with new scaffolds, new modes of action and antivirulence activity has become an important direction in anti-C. albicans drug discovery. Flavonoids are widely distributed natural products with diverse structures and multiple activities, including direct growth inhibition, antivirulence activity, antibiofilm effects, oxidative-stress modulation and antifungal potentiation, making them important resources for screening and structural optimization of novel anti-C. albicans lead compounds. This review summarizes representative flavonoids and related derivatives, including isobavachalcone, baicalein, quercetin, baicalin, phloretin, naringin, hesperetin, equol, xanthohumol, isoflavans and chalcone derivatives, with emphasis on screening sources, antifungal activity, effects on virulence factors and biofilms, mechanisms of action, structural optimization clues and translational prospects. Current evidence indicates that flavonoids can inhibit planktonic C. albicans growth and interfere with adhesion, yeast-to-hypha transition, extracellular hydrolase and polysaccharide production, biofilm formation and mature biofilm development. Their mechanisms involve cell membrane and cell wall damage, disruption of ergosterol homeostasis, excessive reactive oxygen species generation, mitochondrial dysfunction, apoptosis- or autophagy-like death, cAMP-PKA signalling regulation, ENO1/enolase targeting, glycolysis inhibition and efflux-pump interference. From the perspective of structural optimization, the chalcone scaffold, α,β-unsaturated carbonyl group, ortho- or polyphenolic hydroxyl groups, prenyl groups, heterocyclic or halogen substituents and appropriate hydrophobicity are closely associated with enhanced activity. Future studies should strengthen standardized screening, activity evaluation, in vivo efficacy, safety assessment, direct target validation, combination therapy and delivery-system development to promote the translation of flavonoid antifungal leads.