Heterocycle thiazole compounds exhibit antifungal activity through increase in the production of reactive oxygen species in Cryptococcus neoformans/Cryptococcus gattii species complex [PublishAheadOfPrint]

Human cryptococcosis can occur as a primary or opportunistic infection and develops as an acute, sub-acute, or chronic systemic infection, involving different organs of the host. Given the limited therapeutic options and the occasional resistance to fluconazole, there is a need to develop novel drugs for the treatment of cryptococcosis. In this report, we describe promising thiazoles 1, 2, 3, and 4 and explore their possible modes of action against Cryptococcus. To this end, we show evidence of interference in the Cryptococcus antioxidant system. The tested compounds exhibited MIC ranging from 0.25 to 2 μg/mL against C. neoformans H99 and KN99α strains. Interestingly, the knockout strains for cu-oxidase and sarcosine oxidase were resistant to thiazoles. MIC values, mainly, of 1, 2, and 4 against these mutants were higher than for the parental strain. After treatment of C. neoformans ATCC 24067 (=C. deneoformans), and C. gattii L27/01 (=C. deuterogattii) with thiazoles we verified an increase of intracellular ROS. Also, we verified the synergistic interaction among thiazoles and menadione, which generates superoxides, with FIC equal to 0.1874, 0.3024, 0.25, and 0.25 for the thiazoles 1, 2, 3, and 4, respectively. In addition, thiazoles exhibited antagonistic interaction with FeTPPS. Thus, in this work we showed that the action of these thiazoles is related to interference in the antioxidant system. These findings suggest that the oxidative stress may be primarily related to the accumulation of superoxide radicals.

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