Abstract
Several studies have demonstrated the significant antiviral, antimicrobial, antiplasmodial, antioxidative, antifungal, antimutagenic, and antitumor properties of harmine hydrochloride (HMH). The main objective of the present study was to investigate the antifungal effects and underlying mechanisms of HMH when combined with azoles to determine whether such combinations act in a synergistic manner. As a result, we found that HMH exhibits synergistic antifungal effects in combination with azoles against resistant Candida albicans (C. albicans) planktonic cells, as well as resistant C. albicans biofilm in the early stage. Antifungal potential of HMH with fluconazole was also explored in vivo using an invertebrate model. Our results suggest that HMH combined with azoles is synergistic against resistant C. albicans in vitro and in vivo. No synergy is seen with azole sensitive C. albicans strains nor with other Candida species. Such synergistic mechanisms on resistance C. albicans are involved in increasing intracellular azoles, inhibiting hyphal growth, disturbing cytosolic calcium concentration, and inducing apoptosis of resistant C. albicans cells.
Highlights
Despite therapeutic advances, candidiasis remains the most common fungal infection, 50% of which is caused by Candida albicans (C. albicans) (Yapar, 2014; Pu et al, 2017)
No synergism was observed for azole-sensitive C. albicans strains and azole resistant or sensitive strains of other Candida species
The results showed that harmine hydrochloride (HMH) combined with FLC has potential synergistic antifungal effects against the hyphae formation of resistant C. albicans
Summary
Candidiasis remains the most common fungal infection, 50% of which is caused by Candida albicans (C. albicans) (Yapar, 2014; Pu et al, 2017). The choice of appropriate antifungals is very important for patients with the C. albicans infection treatment. Therapies aimed to treat these infections are limited to azoles, polyenes, and echinocandins. Azoles are the most commonly used antifungals due to their better efficacy and higher safety levels. Increases in resistant C. albicans complicate the therapy for C. albicans infections. Managing resistant fungi and discovering drug alternatives against resistant C. albicans are significant challenges for clinical therapy and antifungal drug development. Understanding the inner mechanisms associated with fungal resistance is important for overcoming drug resistance and developing new antifungal agents. The concept of combination antifungal therapy has become a research hotspot (Marr, 2004; Liu et al, 2014). Different drugs or compounds in combination with antifungal are recommended to inhibit C. albicans, especially resistant C. albicans
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