The fluoroquinolone compounds potentiate the antifungal activity of the echinocandins against Aspergillus fumigatus.

IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jin-Ju Choi, Suzie Kang, Yoonseo Lee, Dong-Hyun Lee, Yuju Jang, Ja-Il Goo, Yongseok Choi, Dongho Lee, Cheol-Won Yun
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引用次数: 0

Abstract

The antifungal drugs of the echinocandin family show high efficacy against Aspergillus fumigatus. However, their paradoxical effect, which restores fungal growth at high drug concentrations, and the emergence of resistant strains necessitate improvements. We identified 13 fluoroquinolone compounds from a chemical library containing 10,000 compounds that potentiate the antifungal activity of caspofungin. Among them, NE-E07 significantly enhanced the efficacy of echinocandins against A. fumigatus, including resistant strains, without potentiating other antifungal families like voriconazole or amphotericin B. Specifically, NE-E07 demonstrated a unique ability to potentiate caspofungin's activity against the echinocandin-resistant strain USHM-M0051 isolated from patients. Our experiments revealed that NE-E07, in combination with caspofungin, affected ergosterol biosynthesis in a manner consistent with azole drugs. Docking tests suggest that NE-E07 has a high binding affinity with CYP51, which affects ergosterol biosynthesis similarly to azole drugs. Interestingly, known fluoroquinolones like ciprofloxacin, nalidixic acid, and norfloxacin did not show this potentiating effect, suggesting that NE-E07's unique structure is critical for its activity. Moreover, NE-E07 did not enhance echinocandin activity against Candida albicans or Cryptococcus neoformans, highlighting its specific action against A. fumigatus. In vivo studies demonstrated that co-treatment with NE-E07 and caspofungin increased the survival rate of mice infected with A. fumigatus. This significant improvement in survival underscores the potential clinical relevance of NE-E07 as a co-administered drug with echinocandins for treating fungal infections, particularly those resistant to echinocandins.

氟喹诺酮类化合物增强了棘白菌素对烟曲霉的抗真菌活性。
棘白菌素家族的抗真菌药物对烟曲霉具有较高的抗菌效果。然而,它们的矛盾效应,即在高药物浓度下恢复真菌生长,以及耐药菌株的出现,需要改进。我们从含有10,000种化合物的化学文库中鉴定出13种氟喹诺酮类化合物,这些化合物增强了caspofungin的抗真菌活性。其中,NE-E07显著增强棘球白素对烟曲霉(包括耐药菌株)的药效,而不增强voriconazole或两性霉素b等其他抗真菌家族,特别是NE-E07表现出独特的增强caspofungin对患者分离的棘球白素耐药菌株USHM-M0051的活性的能力。我们的实验表明,NE-E07与caspofungin联用对麦角甾醇生物合成的影响与唑类药物一致。对接试验表明,NE-E07与CYP51具有较高的结合亲和力,其影响麦角甾醇的生物合成与唑类药物相似。有趣的是,已知的氟喹诺酮类药物如环丙沙星、萘啶酸和诺氟沙星没有显示出这种增强作用,这表明NE-E07的独特结构对其活性至关重要。此外,NE-E07对白色念珠菌和新型隐球菌的棘珠菌素活性没有增强作用,说明其对烟芽胞杆菌具有特异性作用。体内研究表明,NE-E07和caspofungin共同作用可提高烟曲霉感染小鼠的存活率。生存率的显著提高强调了NE-E07与棘白菌素合用治疗真菌感染的潜在临床意义,特别是那些对棘白菌素耐药的真菌感染。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Bioscience Reports
Bioscience Reports 生物-细胞生物学
CiteScore
8.50
自引率
0.00%
发文量
380
审稿时长
6-12 weeks
期刊介绍: Bioscience Reports provides a home for sound scientific research in all areas of cell biology and molecular life sciences. Since 2012, Bioscience Reports has been fully Open Access and publishes all papers under the liberal CC BY licence, giving the life science community quality research to share and discuss.Content before 2012 is subscription-only, and is accessible via archive purchase. Articles are assessed on soundness, providing a home for valid findings and data. We welcome papers that span disciplines (e.g. chemistry, medicine), including papers describing: -new methodologies -tools and reagents to probe biological questions -mechanistic details -disease mechanisms -metabolic processes and their regulation -structure and function -bioenergetics
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