Synergistic Effects and Mechanisms of Combined Treatment With Harmine Hydrochloride and Azoles for Resistant Candida albicans

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.