Unveiling the antifungal mechanisms of CTP, a new copper(II)-theophylline/1,10-phenanthroline complex, on drug-resistant non-albicans Candida species

IF 4.1 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Heloisa F. Frota, Pedro F. Barbosa, Carolline M. A. Lorentino, Lorena R. F. Affonso, Lívia S. Ramos, Simone S. C. Oliveira, Lucieri O. P. Souza, Olufunso O. Abosede, Adeniyi S. Ogunlaja, Marta H. Branquinha, André L. S. Santos
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引用次数: 0

Abstract

Candida species undeniably rank as the most prevalent opportunistic human fungal pathogens worldwide, with Candida albicans as the predominant representative. However, the emergence of non-albicans Candida species (NACs) has marked a significant shift, accompanied by rising incidence rates and concerning trends of antifungal resistance. The search for new strategies to combat antifungal-resistant Candida strains is of paramount importance. Recently, our research group reported the anti-Candida activity of a coordination compound containing copper(II) complexed with theophylline (theo) and 1,10-phenanthroline (phen), known as “CTP” – Cu(theo)2phen(H2O).5H2O. In the present work, we investigated the mechanisms of action of CTP against six medically relevant, antifungal-resistant NACs, including C. auris, C. glabrata, C. haemulonii, C. krusei, C. parapsilosis and C. tropicalis. CTP demonstrated significant efficacy in inhibiting mitochondrial dehydrogenases, leading to heightened intracellular reactive oxygen species production. CTP treatment resulted in substantial damage to the plasma membrane, as evidenced by the passive incorporation of propidium iodide, and induced DNA fragmentation as revealed by the TUNEL assay. Scanning electron microscopy images of post-CTP treatment NACs further illustrated profound alterations in the fungal surface morphology, including invaginations, cavitations and lysis. These surface modifications significantly impacted the ability of Candida cells to adhere to a polystyrene surface and to form robust biofilm structures. Moreover, CTP was effective in disassembling mature biofilms formed by these NACs. In conclusion, CTP represents a promising avenue for the development of novel antifungals with innovative mechanisms of action against clinically relevant NACs that are resistant to antifungals commonly used in clinical settings.

Abstract Image

揭示 CTP(一种新的铜(II)-茶碱/1,10-菲啰啉络合物)对耐药非阿氏念珠菌的抗真菌机制。
不可否认,念珠菌是全球最常见的机会性人类真菌病原体,其中以白念珠菌为主要代表。然而,非白念珠菌属(NAC)的出现标志着一个重大转变,伴随着发病率的上升和令人担忧的抗真菌耐药性趋势。寻找抗真菌耐药念珠菌菌株的新策略至关重要。最近,我们的研究小组报道了一种含铜(II)与茶碱(theo)和 1,10-菲罗啉(phen)络合的配位化合物(称为 "CTP" - Cu(theo)2phen(H2O).5H2O)的抗念珠菌活性。在本研究中,我们研究了 CTP 对六种医学相关的、抗真菌耐药的 NAC 的作用机制,包括 C.auris、C.glabrata、C.haemulonii、C.krusei、C.parapsilosis 和 C.tropicalis。CTP 在抑制线粒体脱氢酶方面表现出明显的功效,导致细胞内活性氧生成增加。碘化丙啶的被动掺入证明了 CTP 处理对质膜造成了严重破坏,TUNEL 试验也显示了 CTP 会诱导 DNA 断裂。CTP 处理后 NAC 的扫描电子显微镜图像进一步显示了真菌表面形态的深刻变化,包括内陷、空洞和裂解。这些表面修饰极大地影响了念珠菌细胞粘附到聚苯乙烯表面并形成牢固生物膜结构的能力。此外,CTP 还能有效分解这些 NAC 形成的成熟生物膜。总之,CTP 是开发新型抗真菌药物的一个很有前景的途径,这种药物具有创新的作用机制,可对付对临床常用抗真菌药物具有抗药性的临床相关 NAC。
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来源期刊
Biometals
Biometals 生物-生化与分子生物学
CiteScore
5.90
自引率
8.60%
发文量
111
审稿时长
3 months
期刊介绍: BioMetals is the only established journal to feature the important role of metal ions in chemistry, biology, biochemistry, environmental science, and medicine. BioMetals is an international, multidisciplinary journal singularly devoted to the rapid publication of the fundamental advances of both basic and applied research in this field. BioMetals offers a forum for innovative research and clinical results on the structure and function of: - metal ions - metal chelates, - siderophores, - metal-containing proteins - biominerals in all biosystems. - BioMetals rapidly publishes original articles and reviews. BioMetals is a journal for metals researchers who practice in medicine, biochemistry, pharmacology, toxicology, microbiology, cell biology, chemistry, and plant physiology who are based academic, industrial and government laboratories.
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