Antifungal Effect of All- trans Retinoic Acid against Aspergillus fumigatus In Vitro and in a Pulmonary Aspergillosis In Vivo Model

is the most common opportunistic fungal pathogen and causes invasive pulmonary aspergillosis (IPA), with high mortality among immunosuppressed patients. The fungistatic activity of all- retinoic acid (ATRA) has been recently described We evaluated the efficacy of ATRA and its potential synergistic interaction with other antifungal drugs. A rat model of IPA and experiments were performed to assess the efficacy of ATRA against in association with classical antifungal drugs and studies used to clarify its mechanism of action. ATRA (0.5 and 1 mM) displayed a strong fungistatic activity in 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 , likely by inhibiting fungal heat shock protein 90 ( ) expression and Hsp90-related genes. ATRA treatment reduced mortality in a model of IPA 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.