Molecular Mechanisms Involved in Paradoxal Growth Induced by Caspofungin in Aspergillus fumigatus

Abstract

Invasive aspergillosis infection due to Aspergillus fumigatus specie causes extensive morbidity and mortality, especially among immunosuppressed patients. Caspofungin is a second choice drug to treat aspergilosis, since azole resistant strains have emerged. It belongs to the first class of cell wall-active agents and target the fungal-specific enzyme glucan synthase, which catalyzes the biosynthesis of ²-(1,3)-glucan, a key cell wall polymer. The bottleneck in this treatment is the antifungal paradoxical effect, which has been described as the reversion of growth inhibition at high doses of caspofungin. This effect appears to be a cellular compensatory response to high osmolarity and cell wall integrity pathways, resulting in alteration of cell wall content and structure. However, the impact of the pathways and interactions between all regulatory proteins and transcription factors has not been fully elucidated. In this work we will use effective tools to study, in great detail, the complex cellular actions and protein interactions following caspofungin drug exposure in an effort to optimize the current therapies against invasive aspergillosis.