Dataset Information

Argentilactone molecular targets in Paracoccidioides brasiliensis identified by chemoproteomics

ABSTRACT: 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 lodge in the lungs and may disseminate to other organs/tissues. Treatment of PCM is commonly achieved via administration of antifungals of the azole class, sulfonamides, and amphotericin B. The antifungal toxicity and side effects, added to the long treatment time has driven research for new bioactive compounds. Argentilactone, compound isolated from a Brazilian savanna plant Hyptis ovaliofolia, has been suggested as potent antifungal, inhibiting dimorphism of P. brasiliensis and the enzymatic activity of isocitrate lyase, a key enzyme of the glyoxylate cycle. Furthermore, it has no cytotoxicity and genotoxicity in fibroblast cells at concentrations that inhibit the 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, was the methodology used to explore the interactions between P. brasiliensis proteins and argentilactone

INSTRUMENT(S): nanoACQUITY UPLC

ORGANISM(S): Paracoccidioides Brasiliensis (strain Pb18)

TISSUE(S): Cell Culture, Fungal Cell

DISEASE(S): Paracoccidioidomycosis

SUBMITTER: Lívia Do Carmo Silva

LAB HEAD: Lívia do Carmo Silva

PROVIDER: PXD007680 | Pride | 2018-02-07

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	Pb18_arg_cito_R001.rar	Other
	Pb18_arg_cito_R001_XML.rar	Other
	Pb18_arg_cito_R002.rar	Other
	Pb18_arg_cito_R002_XML.rar	Other
	Pb18_arg_cito_R003.rar	Other

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Publications

Argentilactone Molecular Targets in Paracoccidioides brasiliensis Identified by Chemoproteomics.

Silva Lívia do Carmo LDC Tauhata Sinji Borges Ferreira SBF Baeza Lilian Cristiane LC de Oliveira Cecília Maria Alves CMA Kato Lucília L Borges Clayton Luiz CL de Almeida Soares Célia Maria CM Pereira Maristela M

Antimicrobial agents and chemotherapy 20181024 11

Paracoccidioidomycosis (PCM) is the cause of many deaths from systemic mycoses. The etiological agents of PCM belong to the <i>Paracoccidioides</i> genus, which is restricted to Latin America. The infection is acquired through the inhalation of conidia that primarily lodge in the lungs and may disseminate to other organs and tissues. The treatment for PCM is commonly performed via the administration of antifungals such as amphotericin B, co-trimoxazole, and itraconazole. The antifungal toxicity ...[more]

PMID: 30150478

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Project description:Paracoccidioidomycosis (PCM) is an endemic mycosis in Latin America. The PCM is a systemic disease caused by the thermo dimorphic fungus Paracoccidioides spp, which can exist as mycelia and yeast forms. The mycelia form can be found in environment at temperatures between 18 °C and 25 °C and produces spores or conidia. The PCM infection route occurs by the inhalation of conidia. Once in the lungs, these particles are converted into yeasts pathogenic form. Until now, metabolic aspects and virulence factors related to Paracoccidioides lutzii infective propagule are little understood. In this concern, a global proteomic study of P. lutzii conidia was performed. For conidia production, the mycelia of the isolate Pb01 were cultured in potato agar medium during 90 days at 18 °C. Obtained conidia were collected and purified. The proteins were extracted and subjected to tryptic digestion followed by identification by NanoUPLC-MSE approach. We identified a total of 242 proteins in P. lutzii conidia which were subjected to in silico functional analysis Proteins putatively acting as adhesins, such as GAPDH, enolase, and the glycoprotein β-1,3-glucanosyltransferase (gel2) were identified during our analysis. We also identified proteins related to signal transduction pathways, such as Ras and RhoA GTPases, previously demonstrated to be required for morphologic changes in pathogenic fungi. Proteins related to evasion, defense and virulence were also identified. Proteins acting during temperature shifts or oxidative stress provided by the host environment such as HSP90, catalase, mitochondrial peroxiredoxin Prx1 were identified. It were also identified proteins related to energy production and protein biosynthesis, which can provide important aspects to survival of this resting cells. These results highlight that P. lutzii conidia contain proteins that can contribute to its maintenance in the environment and also molecules related to host-pathogen interactions.

Project description:Azole antifungal agents such as fluconazole exhibit fungistatic activity against Candida albicans. Strategies to enhance azole antifungal activity would be therapeutically appealing. In an effort to identify transcriptional pathways that influence fluconazole susceptibility, we sought to identify transcription factors (TFs) involved in this process. From a collection of C. albicans strains disrupted for genes encoding TFs (Homann et al., PLoS Genet. 2009;5:e1000783), four exhibited a marked reduction in minimum fungicidal concentration (MFC) in both RPMI and YPD media. One of these, UPC2, has been previously characterized with regard to its role in azole susceptibility. Of mutants representing the three remaining TF genes of interest, one (CAS5) was unable to recover from fluconazole exposure at concentrations as low as 2 M-BM-5g/mL after 72 hours in YPD medium. This mutant also showed reduced susceptibility and a clear zone of inhibition by Etest, was unable to grow on solid media containing 10 M-BM-5g/mL fluconazole, and exhibited increased susceptibility by time-kill analysis. CAS5 disruption in highly azole-resistant clinical isolates exhibiting multiple resistance mechanisms did not alter susceptibility. However, CAS5 disruption in strains with specific resistance mutations in ergosterol biosynthesis or efflux pumps resulted in a moderate reduction in MIC and MFC. Genome-wide transcriptional analysis was performed in the presence of fluconazole and was consistent with the suggested role of CAS5 in cell wall organization while also suggesting a role in iron transport and homeostasis. These findings suggest that Cas5 regulates a transcriptional network that influences susceptibility of C. albicans to fluconazole. Further delineation of this transcriptional network may identify targets for potential co-therapeutic strategies to enhance the activity to the azole class of antifungals. We examined the genome-wide gene expression profiles of the wild-type parent strain SC5314 and its cas5M-NM-^T/M-NM-^T derivative in response to fluconazole in order to identify genes whose expression in response to fluconazole is influenced by Cas5.