Aspergillus fumigatus is the most common opportunistic fungal pathogen and causes invasive pulmonary aspergillosis (IPA), with high mortality among immunosuppressed patients. The fungistatic activity of all-trans retinoic acid (ATRA) has been recently described in vitro. We evaluated the efficacy of ATRA in vivo and its potential synergistic interaction with other antifungal drugs. A rat model of IPA and in vitro experiments were performed to assess the efficacy of ATRA against Aspergillus in association with classical antifungal drugs and in silico studies used to clarify its mechanism of action. ATRA (0.5 and 1 mM) displayed a strong fungistatic activity in Aspergillus cultures, while at lower concentrations, synergistically potentiated fungistatic efficacy of subinhibitory concentration of amphotericin B (AmB) and posaconazole (POS). ATRA also enhanced macrophagic phagocytosis of conidia. In a rat model of IPA, ATRA reduced mortality similarly to posaconazole. Fungistatic efficacy of ATRA alone and synergistically with other antifungal drugs was documented in vitro, likely by inhibiting fungal heat shock protein 90 (Hsp90) expression and Hsp90-related genes. ATRA treatment reduced mortality in a model of IPA in vivo. Those findings suggest ATRA as a suitable fungistatic agent that can also reduce dosage and adverse reactions of classical antifungal drugs and add to the development of new therapeutic strategies against IPA and systemic fungal infections.

中文翻译：

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全反式维甲酸对烟曲霉的体外和体内肺曲霉病的抗真菌作用。

烟曲霉是最常见的机会性真菌病原体，可引起侵袭性肺曲霉病（IPA），在免疫抑制患者中死亡率很高。最近已经在体外描述了全反式维甲酸（ATRA）的抑菌活性。我们评估了ATRA在体内的功效及其与其他抗真菌药物的潜在协同相互作用。进行了IPA大鼠模型和体外实验，以评估ATRA对抗曲霉菌的功效以及经典的抗真菌药物和计算机模拟研究，以阐明其作用机理。ATRA（0.5和1 mM）表现出很强的抑菌活性在较低浓度的曲霉菌培养物中，亚抑制浓度的两性霉素B（AmB）和泊沙康唑（POS）具有协同增效的抑菌功效。ATRA还增强了分生孢子的巨噬细胞吞噬作用。在IPA大鼠模型中，ATRA与泊沙康唑相似地降低了死亡率。单独或与其他抗真菌药物协同作用的ATRA的抑菌功效已在体外记录，可能是通过抑制真菌热休克蛋白90（Hsp90）的表达和与Hsp90相关的基因。ATRA治疗可降低IPA体内模型的死亡率。这些发现表明，ATRA是一种合适的抑菌剂，还可以减少传统抗真菌药的剂量和不良反应，并增加了针对IPA和全身性真菌感染的新治疗策略的开发。