The Inhibitory Effect of Validamycin A on Aspergillus flavus
Napasawan Plabutong1,2, Supanuch Ekronarongchai1, Nattarika Niwetbowornchai1
1Medical Microbiology, Interdisciplinary Program, Graduate School, Chulalongkorn University, Bangkok, Thailand.
Abstract:
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.
Insights
Validamycin A inhibits Aspergillus flavus growth and germination. Combined with amphotericin B, it shows synergistic effects against resistant strains, offering a potentially safer treatment for fungal infections.
Area of Science:
- Mycology
- Antimicrobial research
- Drug discovery
Background:
- Aspergillus flavus is a common cause of fungal infections.
- Current antifungal treatments have significant side effects.
- Validamycin A, a trehalase inhibitor, is used agriculturally but its therapeutic potential is unexplored.
Purpose of the Study:
- To investigate the antifungal activity of validamycin A against Aspergillus flavus.
- To evaluate the synergistic effect of validamycin A in combination with amphotericin B.
- To assess the cytotoxicity of validamycin A on human bronchial epithelial cells.
Main Methods:
- Checkerboard assays were used to determine the minimum inhibitory concentrations (MICs) and fractional inhibitory concentration indices (FICIs).
- Trehalose levels and conidial germination were measured in A. flavus treated with validamycin A.
- LDH-cytotoxicity assays assessed the effect of validamycin A on human bronchial epithelial cells.
Main Results:
- Validamycin A increased trehalose levels, delayed germination, and reduced adherence of A. flavus conidia.
- A synergistic antifungal effect was observed when validamycin A was combined with amphotericin B against resistant A. flavus strains.
- Validamycin A exhibited no significant cytotoxicity in human bronchial epithelial cells.
Conclusions:
- Validamycin A demonstrates antifungal properties against Aspergillus flavus, inhibiting growth and germination.
- The combination of validamycin A and amphotericin B exhibits synergistic activity, enhancing fungal killing.
- Validamycin A presents a promising therapeutic candidate for treating Aspergillus flavus infections with a favorable safety profile.
