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Ambroxol Hydrochloride Combined with Fluconazole Reverses the Resistance of Candida albicans to Fluconazole

View Article: PubMed Central - PubMed

ABSTRACT

In this study, we found that ambroxol hydrochloride (128 μg/mL) exhibits synergistic antifungal effects in combination with fluconazole (2 μg/mL) against resistant planktonic Candida albicans (C. albicans) cells. This combination also exhibited synergistic effects against resistant C. albicans biofilms in different stages (4, 8, and 12 h) according to the microdilution method. In vitro data were further confirmed by the success of this combination in treating Galleria mellonella infected by resistant C. albicans. With respect to the synergistic mechanism, our result revealed that ambroxol hydrochloride has an effect on the drug transporters of resistant C. albicans, increasing the uptake and decreasing the efflux of rhodamine 6G, a fluorescent alternate of fluconazole. This is the first study to investigate the in vitro and in vivo antifungal effects, as well as the possible synergistic mechanism of ambroxol hydrochloride in combination with fluconazole against resistant C. albicans. The results show the potential role for this drug combination as a therapeutic alternative to treat resistant C. albicans and provide insights into the development of antifungal targets and new antifungal agents.

No MeSH data available.


Effect of FLC alone or in combination with ABH on the survival of infected G. mellonella over 4 days. The concentration of yeast cells was 5 × 106 CFU/larva. Treatments consisted of PBS, FLC (1.6 μg/larva) alone, ABH (3.2 μg/larva) alone, or a combination of FLC (1.6 μg/larva) with ABH (3.2 μg/larva). The Statistical Product and Service Solutions 20 software was used to analyze the data. The experiments were performed three times on different days.
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Figure 1: Effect of FLC alone or in combination with ABH on the survival of infected G. mellonella over 4 days. The concentration of yeast cells was 5 × 106 CFU/larva. Treatments consisted of PBS, FLC (1.6 μg/larva) alone, ABH (3.2 μg/larva) alone, or a combination of FLC (1.6 μg/larva) with ABH (3.2 μg/larva). The Statistical Product and Service Solutions 20 software was used to analyze the data. The experiments were performed three times on different days.

Mentions: Following the identification of the synergism between FLC and ABH in vitro, experiments were designed to identify whether this effect would be replicated in vivo. In the preliminary survival assay, all uninfected G. mellonella larvae in four groups (PBS, FLC, ABH, and drug combination) were alive after 4 days, indicating that PBS and the drugs have no harmful effect on G. mellonella. The effect of the drugs alone or in combination on the survival rates, fungal burden and histopathology of infected larvae is shown in Figures 1–3, respectively. When used alone, the drugs, FLC and ABH had no significant effect on the survival rates of infected larvae. However, their combination significantly improved the survival rates, confirming the efficacy of this drug combination in vivo (Figure 1). Encouragingly, the combination of FLC and ABH resulted in a greater reduction in fungal burden compared to the control and individual drug groups, as shown by the slower proliferation of C. albicans in the group receiving the drug combination over 4 days (Figure 2). Slices of infected larvae in four groups revealed a significant decrease in the number of melanized nodules in larvae treated with this drug combination, compared to no drug or larvae treated with individual drugs (Figure 3). The histopathology results are in agreement with the survival rates and fungal burden experiments, which further confirms the synergistic effects of FLC and ABH combination against resistant C. albicans in vivo.


Ambroxol Hydrochloride Combined with Fluconazole Reverses the Resistance of Candida albicans to Fluconazole
Effect of FLC alone or in combination with ABH on the survival of infected G. mellonella over 4 days. The concentration of yeast cells was 5 × 106 CFU/larva. Treatments consisted of PBS, FLC (1.6 μg/larva) alone, ABH (3.2 μg/larva) alone, or a combination of FLC (1.6 μg/larva) with ABH (3.2 μg/larva). The Statistical Product and Service Solutions 20 software was used to analyze the data. The experiments were performed three times on different days.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5383865&req=5

Figure 1: Effect of FLC alone or in combination with ABH on the survival of infected G. mellonella over 4 days. The concentration of yeast cells was 5 × 106 CFU/larva. Treatments consisted of PBS, FLC (1.6 μg/larva) alone, ABH (3.2 μg/larva) alone, or a combination of FLC (1.6 μg/larva) with ABH (3.2 μg/larva). The Statistical Product and Service Solutions 20 software was used to analyze the data. The experiments were performed three times on different days.
Mentions: Following the identification of the synergism between FLC and ABH in vitro, experiments were designed to identify whether this effect would be replicated in vivo. In the preliminary survival assay, all uninfected G. mellonella larvae in four groups (PBS, FLC, ABH, and drug combination) were alive after 4 days, indicating that PBS and the drugs have no harmful effect on G. mellonella. The effect of the drugs alone or in combination on the survival rates, fungal burden and histopathology of infected larvae is shown in Figures 1–3, respectively. When used alone, the drugs, FLC and ABH had no significant effect on the survival rates of infected larvae. However, their combination significantly improved the survival rates, confirming the efficacy of this drug combination in vivo (Figure 1). Encouragingly, the combination of FLC and ABH resulted in a greater reduction in fungal burden compared to the control and individual drug groups, as shown by the slower proliferation of C. albicans in the group receiving the drug combination over 4 days (Figure 2). Slices of infected larvae in four groups revealed a significant decrease in the number of melanized nodules in larvae treated with this drug combination, compared to no drug or larvae treated with individual drugs (Figure 3). The histopathology results are in agreement with the survival rates and fungal burden experiments, which further confirms the synergistic effects of FLC and ABH combination against resistant C. albicans in vivo.

View Article: PubMed Central - PubMed

ABSTRACT

In this study, we found that ambroxol hydrochloride (128 μg/mL) exhibits synergistic antifungal effects in combination with fluconazole (2 μg/mL) against resistant planktonic Candida albicans (C. albicans) cells. This combination also exhibited synergistic effects against resistant C. albicans biofilms in different stages (4, 8, and 12 h) according to the microdilution method. In vitro data were further confirmed by the success of this combination in treating Galleria mellonella infected by resistant C. albicans. With respect to the synergistic mechanism, our result revealed that ambroxol hydrochloride has an effect on the drug transporters of resistant C. albicans, increasing the uptake and decreasing the efflux of rhodamine 6G, a fluorescent alternate of fluconazole. This is the first study to investigate the in vitro and in vivo antifungal effects, as well as the possible synergistic mechanism of ambroxol hydrochloride in combination with fluconazole against resistant C. albicans. The results show the potential role for this drug combination as a therapeutic alternative to treat resistant C. albicans and provide insights into the development of antifungal targets and new antifungal agents.

No MeSH data available.