氟喹诺酮类化合物可增强棘白菌素类药物对烟曲霉的抗真菌活性。

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

作者信息

Choi Jin-Ju, Kang Suzie, Lee Yoonseo, Lee Dong-Hyun, Jang Yuju, Goo Ja-Il, Choi Yongseok, Lee Dongho, Yun Cheol-Won

机构信息

School of Life Sciences and Biotechnology, Korea University, Anam-dong, Sungbuk-gu, Seoul, Republic of Korea.

EsgelBio Co, Anam-dong, Sungbuk-gu, Seoul, Republic of Korea.

出版信息

Biosci Rep. 2025 Feb 4;45(2):BSR20250001. doi: 10.1042/BSR20250001.

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.

摘要

棘白菌素类抗真菌药物对烟曲霉显示出高疗效。然而,它们在高药物浓度下恢复真菌生长的矛盾效应以及耐药菌株的出现使得有必要进行改进。我们从一个包含10000种化合物的化学文库中鉴定出13种氟喹诺酮化合物,这些化合物可增强卡泊芬净的抗真菌活性。其中,NE-E07显著增强了棘白菌素类药物对烟曲霉(包括耐药菌株)的疗效,而不会增强伏立康唑或两性霉素B等其他抗真菌药物家族的疗效。具体而言,NE-E07表现出独特的能力,可增强卡泊芬净对从患者分离出的棘白菌素耐药菌株USHM-M0051的活性。我们的实验表明,NE-E07与卡泊芬净联合使用时,以与唑类药物一致的方式影响麦角固醇生物合成。对接试验表明,NE-E07与CYP51具有高结合亲和力,其对麦角固醇生物合成的影响与唑类药物相似。有趣的是,环丙沙星、萘啶酸和诺氟沙星等已知氟喹诺酮类药物未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并未增强棘白菌素类药物对白色念珠菌或新型隐球菌的活性,突出了其对烟曲霉的特异性作用。体内研究表明,NE-E07与卡泊芬净联合治疗可提高感染烟曲霉小鼠的存活率。存活率的显著提高强调了NE-E07作为与棘白菌素类药物联合使用治疗真菌感染(特别是对棘白菌素耐药的感染)的潜在临床相关性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc33/12096952/d33a8bafe26e/bsr-45-02-bsr-2025-0001-g001.jpg

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