Argentilactone molecular targets in Paracoccidioides brasiliensis identified by chemoproteomics

Abstract

Paracoccidioidomycosis (PCM) is the cause of many deaths from sys-temic mycoses. The etiological agents of PCM belong to theParacoccidioidesgenus,which is restricted to Latin America. The infection is acquired through the inhalationof conidia that primarily lodge in the lungs and may disseminate to other organsand tissues. The treatment for PCM is commonly performed via the administration ofantifungals such as amphotericin B, co-trimoxazole, and itraconazole. The antifungaltoxicity and side effects, in addition to their long treatment times, have stimulatedresearch for new bioactive compounds. Argentilactone is a compound that was iso-lated from the Brazilian savanna plantHyptis ovalifolia, and it has been suggested tobe a potent antifungal, inhibiting the dimorphism ofP. brasiliensisand the enzy-matic activity of isocitrate lyase, a key enzyme of the glyoxylate cycle. This work wasdeveloped due to the importance of elucidating the putative mode of action of ar-gentilactone. The chemoproteomics approach via affinity chromatography was themethodology used to explore the interactions betweenP. brasiliensisproteins andargentilactone. A total of 109 proteins were identified and classified functionally. Themost representative functional categories were related to amino acid metabolism,energy, and detoxification. Argentilactone inhibited the enzymatic activity of malatedehydrogenase, citrate synthase, and pyruvate dehydrogenase. Furthermore, argenti-lactone induces the production of reactive oxygen species and inhibits the biosyn-thesis of cell wall polymers.