Combining Fluconazole with Benzo[a]phenoxazine Derivatives as a Promising Strategy Against Fluconazole-Resistant Candida Species.

IF 4.2 2区 化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecules Pub Date : 2024-11-02 DOI:10.3390/molecules29215197
Maria Inês Pacheco, Bárbara Guimarães, Patrícia Pereira-Silva, Augusto Costa-Barbosa, M Sameiro T Gonçalves, Maria João Sousa, Paula Sampaio
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Abstract

The rise in non-albicans Candida species, exhibiting unpredictable antifungal resistance, complicates treatment and contributes to the growing threat of invasive, life-threatening infections. This study evaluates the antifungal activity of four benzo[a]phenoxazine derivatives (C34, C35, A42, and A44) against 14 Candida strains following EUCAST standards. Fluconazole interactions are analysed through fractional inhibitory concentration index (FICI) calculation and response surface analysis based on the Bliss model. Macrophage-like J774A.1 cells are used to assess Candida killing in the presence of synergistic compounds. The MIC values against the different strains vary, with C34 showing the strongest activity, followed by C35, while A42 has the highest MIC values, indicating lower efficacy. However, A42 demonstrates the best synergy with fluconazole against fluconazole-resistant Candida strains. Cytotoxicity assays reveal that the chloropropyl group present in C35 and A42 enhances cytocompatibility. Co-culture with macrophages shows significant yeast killing for C. albicans and C. auris when fluconazole and A42 are combined, requiring concentrations 4 and 16 times lower than their MIC values, enhancing antifungal activity. Given fluconazole's fungistatic nature and the emergence of drug-resistant strains, benzo[a]phenoxazine derivatives' ability to enhance fluconazole's efficacy present a promising strategy to address antifungal resistance in critical pathogens. These findings align with global research priorities, offering new potential avenues for developing more effective antifungal therapies.

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将氟康唑与苯并[a]吩噁嗪衍生物结合起来,作为一种对付氟康唑耐药念珠菌菌种的有效策略
表现出不可预测的抗真菌耐药性的非阿氏类念珠菌的增加使治疗变得更加复杂,并导致威胁生命的侵袭性感染的威胁不断增加。本研究评估了四种苯并[a]吩噁嗪衍生物(C34、C35、A42 和 A44)对 14 种念珠菌菌株的抗真菌活性,这些衍生物符合 EUCAST 标准。通过分数抑制浓度指数(FICI)计算和基于 Bliss 模型的响应面分析,分析了氟康唑的相互作用。巨噬细胞类 J774A.1 细胞用于评估协同化合物存在时对念珠菌的杀伤力。针对不同菌株的 MIC 值各不相同,C34 显示出最强的活性,其次是 C35,而 A42 的 MIC 值最高,表明药效较低。不过,A42 与氟康唑对耐氟康唑的念珠菌菌株的协同作用最好。细胞毒性试验表明,C35 和 A42 中的氯丙基增强了细胞相容性。与巨噬细胞共培养显示,当氟康唑和 A42 结合使用时,可显著杀死白念珠菌和栗色念珠菌,所需的浓度分别比其 MIC 值低 4 倍和 16 倍,从而增强了抗真菌活性。鉴于氟康唑的杀真菌性和耐药菌株的出现,苯并[a]吩噁嗪衍生物增强氟康唑药效的能力为解决关键病原体的抗真菌耐药性问题提供了一种前景广阔的策略。这些发现与全球研究重点一致,为开发更有效的抗真菌疗法提供了新的潜在途径。
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来源期刊
Molecules
Molecules 化学-有机化学
CiteScore
7.40
自引率
8.70%
发文量
7524
审稿时长
1.4 months
期刊介绍: Molecules (ISSN 1420-3049, CODEN: MOLEFW) is an open access journal of synthetic organic chemistry and natural product chemistry. All articles are peer-reviewed and published continously upon acceptance. Molecules is published by MDPI, Basel, Switzerland. Our aim is to encourage chemists to publish as much as possible their experimental detail, particularly synthetic procedures and characterization information. There is no restriction on the length of the experimental section. In addition, availability of compound samples is published and considered as important information. Authors are encouraged to register or deposit their chemical samples through the non-profit international organization Molecular Diversity Preservation International (MDPI). Molecules has been launched in 1996 to preserve and exploit molecular diversity of both, chemical information and chemical substances.
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