The prevalence of multidrug resistance has been increasingly witnessed during the past few decades. Resistance of human pathogenic fungi against the currently available antifungal agents has increased the frequency of fungal infections and associated mortality rates. The discovery of novel lead antifungal agents is important to challenge multidrug resistance. The present study examined the antifungal potential of chemically synthesized β-Nitrostyrene derivatives. Among the eight β-Nitrostyrene derivatives used in this study, SS45, SS46 and SS47 showed strong antifungal potential. The results show that β-Nitrostyrene derivatives inhibited the growth of different species of human pathogenic Candida, particularly the highly prevalent C. albicans, C. glabrata and the emerging pathogenic C. auris species. Moreover, β-Nitrostyrene derivatives also show strong antifungal activities against drug-resistant clinical isolates and drug transporter overexpressing fungal species. The drug susceptibility assays revealed that β-Nitrostyrene derivatives are fungicidal and show the synergy of action when combined with antifungal drugs caspofungin and fluconazole. The transcriptomic study performed on C. albicans in the presence of β-Nitrostyrene derivatives revealed the differential expression of genes related to cell wall metabolism. Mechanistically, β-Nitrostyrene derivatives impact cell wall morphology, enhance ROS generation and modulate drug efflux. Collectively this study reveals that β-Nitrostyrene derivatives have strong antifungal potential with a particular mode of activity similar to known cell wall perturbing antifungal agents and thus can be exploited as promising potential antifungal agents for further studies.

在过去的几十年中，多药耐药性的流行越来越明显。人类病原真菌对目前可用的抗真菌剂的耐药性增加了真菌感染的频率和相关的死亡率。新型先导抗真菌药物的发现对于挑战多药耐药性具有重要意义。本研究检测了化学合成的 β-硝基苯乙烯衍生物的抗真菌潜力。在本研究中使用的八种 β-硝基苯乙烯衍生物中，SS45、SS46 和 SS47 显示出很强的抗真菌潜力。结果表明，β-硝基苯乙烯衍生物抑制了不同种类的人类致病性念珠菌的生长，特别是高度流行的白色念珠菌、光滑念珠菌和新出现的致病性耳念珠菌。而且，β-硝基苯乙烯衍生物对耐药临床分离株和药物转运蛋白过表达的真菌物种也显示出很强的抗真菌活性。药敏试验表明，β-硝基苯乙烯衍生物具有杀菌作用，与抗真菌药物卡泊芬净和氟康唑合用时表现出协同作用。在存在 β-硝基苯乙烯衍生物的情况下对白色念珠菌进行的转录组学研究揭示了与细胞壁代谢相关的基因的差异表达。从机理上讲，β-硝基苯乙烯衍生物影响细胞壁形态，增强 ROS 生成并调节药物流出。