探索新型氨基甲酸酯衍生物作为抗新兴超级病菌耳念珠菌的有前景候选药物的抗真菌潜力。
Exploring the antifungal potential of novel carbazate derivatives as promising drug candidates against emerging superbug, Candida auris.
作者信息
Fatima Tazeen, Fatima Zeeshan, Billamboz Muriel, Hameed Saif
机构信息
Amity Institute of Biotechnology, Amity University Haryana, Gurugram Manesar 122413, India.
ICL, JUNIA, Université Catholique de Lille, LITL, F-59000 Lille, France.
出版信息
Bioorg Chem. 2024 Dec;153:107782. doi: 10.1016/j.bioorg.2024.107782. Epub 2024 Sep 4.
Candida auris (C. auris) has caused notable outbreaks across the globe in last decade and emerged as a life-threatening human pathogenic fungus. Despite significant advances in antifungal research, the drug resistance mechanisms in C. auris still remain elusive. Under such pressing circumstances, research on identification of new antifungal compounds is of immense interest. Thus, our studies aimed at identifying novel drug candidates and elucidate their biological targets in C. auris. After screening of several series of synthetic and hemisynthetic compounds from JUNIA chemical library, compounds C4 (butyl 2-(4-chlorophenyl)hydrazine-1-carboxylate) and C13 (phenyl 2-(4-chlorophenyl) hydrazine-1-carboxylate), belonging to the carbazate series, were identified to display considerable antifungal activities against C. auris as well as its fluconazole resistant isolates. Elucidation of biological targets revealed that C4 and C13 lead to changes in polysaccharide composition of the cell wall and disrupt vacuole homeostasis. Mechanistic insights further unravelled inhibited efflux pump activities of ATP binding cassette transporters and depleted ergosterol content. Additionally, C4 and C13 cause mitochondrial dysfunction and confer oxidative stress. Furthermore, both C4 and C13 impair biofilm formation in C. auris. The in vivo efficacy of C4 and C13 were demonstrated in Caenorhabditis elegans model after C. auris infection showing reduced mortality of the nematodes. Together, promising antifungal properties were observed for C4 and C13 against C. auris that warrant further investigations. To summarise, collected data pave the way for the design and development of future first-in-class antifungal drugs.
耳念珠菌(C. auris)在过去十年中已在全球范围内引发了显著的疫情,并成为一种威胁生命的人类致病真菌。尽管抗真菌研究取得了重大进展,但耳念珠菌的耐药机制仍然难以捉摸。在这种紧迫的情况下,新型抗真菌化合物的鉴定研究备受关注。因此,我们的研究旨在鉴定新型候选药物并阐明其在耳念珠菌中的生物学靶点。从JUNIA化学库中筛选了几系列合成和半合成化合物后,属于氨基甲酸酯系列的化合物C4(2-(4-氯苯基)肼-1-羧酸丁酯)和C13(2-(4-氯苯基)肼-1-羧酸苯酯)被鉴定出对耳念珠菌及其氟康唑耐药菌株具有显著的抗真菌活性。生物学靶点的阐明表明,C4和C13导致细胞壁多糖组成的变化并破坏液泡稳态。机理研究进一步揭示了ATP结合盒转运蛋白的外排泵活性受到抑制以及麦角固醇含量减少。此外,C4和C13导致线粒体功能障碍并引发氧化应激。此外,C4和C13均损害耳念珠菌中的生物膜形成。在耳念珠菌感染后的秀丽隐杆线虫模型中证明了C4和C13的体内疗效,显示出线虫的死亡率降低。总之,观察到C4和C13对耳念珠菌具有有前景的抗真菌特性,值得进一步研究。综上所述,收集到的数据为未来一流抗真菌药物的设计和开发铺平了道路。