Aspergillus flavus is one of the most common isolates from patients with
fungal infections.
Aspergillus infection is usually treated with
antifungal agents, but side effects of these agents are common.
Trehalase is an essential
enzyme involved in fungal metabolism, and the
trehalase inhibitor,
validamycin A, has been used to prevent
fungal infections in agricultural products. In this study, we observed that
validamycin A significantly increased
trehalose levels in A. flavus conidia and delayed germination, including decreased fungal adherence. In addition,
validamycin A and
amphotericin B showed a combinatorial effect on A. flavus ATCC204304 and clinical isolates with high minimum inhibitory concentrations (MICs) of
amphotericin B using checkerboard assays. We observed that
validamycin A and
amphotericin B had a synergistic effect on A. flavus strains resistant to
amphotericin B. The MICs in the combination of
validamycin A and
amphotericin B were at 0.125 μg/mL and 2 μg/mL, respectively. The FICI of
validamycin A and
amphotericin B of these clinical isolates was about 0.25-0.28 with synergistic effects. No
drug cytotoxicity was observed in human bronchial epithelial cells treated with
validamycin A using LDH-cytotoxicity assays. In conclusion, this study demonstrated that
validamycin A inhibited the growth of A. flavus and delayed conidial germination. Furthermore, the combined effect of
validamycin A with
amphotericin B increased A. flavus killing, without significant cytotoxicity to human bronchial epithelial cells. We propose that
validamycin A could potentially be used in vivo as an alternative treatment for A. flavus
infections.