Anti-cryptococcal Synergistic Activity of the Association between Amphotericin B and n-hexane Extract from Brazilian Red Propolis

More than half a century after the introduction of amphotericin B (AmpB), the cryptococcosis treatment remains unsatisfactory. This disease, caused by yeasts of the genus Cryptococcus , is responsible for a considerable mortality rate and morbidity, mainly due to the adverse effects arising from the treatment which is limited to AmpB used in combination with other antifungals, such as voriconazole. Due to these factors, therapeutic alternatives have been investigated, either by association with other classes of antifungals or by combination with natural compounds. Propolis is a complex resinous mixture produced by bees and its antimicrobial activity has been intensely investigated. Among the different types of propolis, Brazilian red propolis has been shown antifungal activity. However, little is known about its anti- Cryptococcus activity. The main objective of this study was to investigate the ability of the n -hexane extract of Brazilian red propolis (hex-BRP) to act against clinical strains of Cryptococcus neoformans and analyze the synergism with AmpB through the checkerboard method. The hex - BRP extract exhibited minimal inhibitory concentrations between 7.81 µg/ml and 1.95 µg/ml. The hex - BRP and AmpB showed synergy and additivity against four strains of clinical origin of Cryptococcus neoformans . These findings point to hex-BRP as an important therapeutic strategy, since it caused a reduction in the dose of AmpB from 0.125 µg/ml to 0.031 µg/ml, and may reduce the nephrotoxicity in the population treated with this medicine. It is worth mentioning that these results are promising and the activity was superior to that demonstrated by the classic combination with flucytosine.