Antifungal activity of liriodenine on agents of systemic mycoses, with emphasis on the genus Paracoccidioides

Abstract

Background: Endemic systemic mycoses remain a health challenge, since these opportunistic diseases are increasingly infecting immunosuppressed patients. The simultaneous use of antifungal compounds and other drugs to treat infectious or non-infectious diseases has led to several interactions and undesirable effects. Thus, new antifungal compounds should be investigated. The present study aimed to evaluate the activity of liriodenine extracted from Annona macroprophyllata on agents of systemic mycoses, with emphasis on the genus Paracoccidioides . Methods: The minimum inhibitory concentration (MIC) and minimum fungicide concentration (MFC) were determined by the microdilution method. The cellular alterations caused by liriodenine on a standard P. brasiliensis (Pb18) strain were evaluated by transmission and scanning electron microscopy. Results: Liriodenine was effective only in 3 of the 8 strains of the genus Paracoccidioides and in the Histoplasma capsulatum strain, in a very low concentration (MIC of 1.95 μg.mL -1 ); on yeasts of Candida spp. (MIC of 125 to 250 μg.mL-1), including C. krusei (250 μg.mL -1 ), which has intrinsic resistance to fluconazole; and in Cryptococcus neoformans and Cryptococcus gattii (MIC of 62.5 μg.mL -1 ). However, liriodenine was not effective against Aspergillus fumigatus at the studied concentrations. Liriodenine exhibited fungicidal activity against all standard strains and clinical isolates that showed to be susceptible by in vitro tests. Electron microscopy revealed cytoplasmic alterations and damage to the cell wall of P. brasiliensis (Pb18). Conclusion: Our results indicate that liriodenine is a promising fungicidal compound that should undergo further investigation with some chemical modifications.

Antifungal activity of liriodenine on clinical strains of Cryptococcus neoformans and Cryptococcus gattii species complexes

“…The previous findings with liriodenine based on MFC [ 18 ] were confirmed by the present study, in which the time-kill methodology was carried out. In addition, the intense morphological alterations demonstrated by TEM - suggestive of killed cryptococcal cells - seem to justify liriodenine fungicidal activity.…”

“…In spite of the well-conducted studies on the treatment of cryptococcal meningitis, many questions still remain unanswered in the clinical practice, stimulating the investigation of new compounds, such as liriodenine [ 6 - 8 , 29 , 30 ]. The choice of this compound was based on some previous information: (a) liriodenine is extracted from Annona mucosa , a plant available in the Brazilian region where our university is located; (b) liriodenine extraction was performed in this university; (c) its chemical composition is known, making it easier to have a possible future production and modification of the molecule; (d) the literature review revealed some antimicrobial activity; (e) our previous study showed its activity on some fungi, mainly from the Cryptococcus genus [ 18 ].…”

“…Transmission electron microscopy (TEM) was performed at the Center of Electron Microscopy of São Paulo State University (UNESP), Botucatu Biosciences Institute (São Paulo state, Brazil), regarding its previously reported specifications [ 18 ].…”

“…Each animal received 0.120 mL of the liriodenine-containing solution. The doses used were defined based on the results of the in vitro sensitivity test [ 18 ]. Two uninfected mice received 0.75 mg.kg -1 and other two 1.50 mg.kg -1 of liriodenine in a single dose.…”

“…Levorato-Vinche et al [ 18 ] evaluated the in vitro antifungal activity of liriodenine on agents of systemic mycoses, and it showed a minimum inhibitory concentration (MIC) of 62.5 µg.mL -1 on most of the isolates. Moreover, its activity was fungicidal on susceptible isolates.…”