Argentilactone molecular targets in Paracoccidioides brasiliensis identified by chemoproteomics

ABSTRACT: Paracoccidioidomycosis (PCM) is the cause of several deaths from systemic mycoses. The etiological agents of PCM belong to the Paracoccidioides genus, which is restricted to Latin America. The infection is acquired through inhalation of conidia that primarily lodges in the lungs and may disseminate to other organs/tissues. Treatment of PCM is commonly achieved via the administration of antifungals such as amphotericin B, co-trimoxazole, and itraconazole. The antifungal toxicity and side effects, in addition to the long treatment time, have driven research for new bioactive compounds. Argentilactone, a compound isolated from the Brazilian savanna plant Hyptis ovaliofolia, has been suggested to be a potent antifungal, inhibiting the dimorphism of P. brasiliensis and enzymatic activity of isocitrate lyase, a key enzyme of the glyoxylate cycle. Furthermore, argentilactone has no cytotoxicity and genotoxicity in fibroblast cells at concentrations that inhibit fungal growth. This work was developed due to the importance of elucidating the putative mode of action of argentilactone. The chemoproteomics approach, by affinity chromatography, is the methodology used to explore the interactions between P. brasiliensis proteins and argentilactone. A total of 109 proteins was identified and classified functionally, with those related to amino acid metabolism, energy, and detoxification being the most representative. The interactome of argentilactone binding proteins was predicted. Argentilactone inhibited the enzymatic activity of malate dehydrogenase, citrate synthase, and pyruvate dehydrogenase. Furthermore, argentilactone induced the production of reactive oxygen species. In addition, our data were compared to previously obtained proteomics and transcriptional data. Altogether, our results reveal argentilactone as a promising antifungal.

INSTRUMENT(S): nanoACQUITY UPLC

ORGANISM(S): Fungal Sp. 5ol6-6pl1

TISSUE(S): Fungal Cell

DISEASE(S): Paracoccidioidomycosis

SUBMITTER: Lívia Do Carmo Silva  

LAB HEAD: Lívia do Carmo Silva

PROVIDER: PXD008858 | Pride | 2018-02-07

REPOSITORIES: Pride