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1.
Nucleic Acids Res ; 48(D1): D642-D649, 2020 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-31586406

RESUMEN

The YEASTRACT+ information system (http://YEASTRACT-PLUS.org/) is a wide-scope tool for the analysis and prediction of transcription regulatory associations at the gene and genomic levels in yeasts of biotechnological or human health relevance. YEASTRACT+ is a new portal that integrates the previously existing YEASTRACT (http://www.yeastract.com/) and PathoYeastract (http://pathoyeastract.org/) databases and introduces the NCYeastract (Non-Conventional Yeastract) database (http://ncyeastract.org/), focused on the so-called non-conventional yeasts. The information in the YEASTRACT database, focused on Saccharomyces cerevisiae, was updated. PathoYeastract was extended to include two additional pathogenic yeast species: Candida parapsilosis and Candida tropicalis. Furthermore, the NCYeastract database was created, including five biotechnologically relevant yeast species: Zygosaccharomyces baillii, Kluyveromyces lactis, Kluyveromyces marxianus, Yarrowia lipolytica and Komagataella phaffii. The YEASTRACT+ portal gathers 289 706 unique documented regulatory associations between transcription factors (TF) and target genes and 420 DNA binding sites, considering 247 TFs from 10 yeast species. YEASTRACT+ continues to make available tools for the prediction of the TFs involved in the regulation of gene/genomic expression. In this release, these tools were upgraded to enable predictions based on orthologous regulatory associations described for other yeast species, including two new tools for cross-species transcription regulation comparison, based on multi-species promoter and TF regulatory network analyses.


Asunto(s)
Biología Computacional/métodos , Bases de Datos Genéticas , Regulación Fúngica de la Expresión Génica , Genoma Fúngico , Genómica , Levaduras/genética , Sitios de Unión , Candida tropicalis/genética , Redes Reguladoras de Genes , Kluyveromyces/genética , Filogenia , Regiones Promotoras Genéticas , Saccharomyces cerevisiae/genética , Programas Informáticos , Especificidad de la Especie , Factores de Transcripción/genética , Transcripción Genética , Yarrowia/genética , Zygosaccharomyces/genética
2.
Int J Mol Sci ; 22(3)2021 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-33573089

RESUMEN

Candida glabrata is an emerging fungal pathogen whose success depends on its ability to resist antifungal drugs but also to thrive against host defenses. In this study, the predicted multidrug transporter CgTpo4 (encoded by ORF CAGL0L10912g) is described as a new determinant of virulence in C. glabrata, using the infection model Galleria mellonella. The CgTPO4 gene was found to be required for the C. glabrata ability to kill G. mellonella. The transporter encoded by this gene is also necessary for antimicrobial peptide (AMP) resistance, specifically against histatin-5. Interestingly, G. mellonella's AMP expression was found to be strongly activated in response to C. glabrata infection, suggesting AMPs are a key antifungal defense. CgTpo4 was also found to be a plasma membrane exporter of polyamines, especially spermidine, suggesting that CgTpo4 is able to export polyamines and AMPs, thus conferring resistance to both stress agents. Altogether, this study presents the polyamine exporter CgTpo4 as a determinant of C. glabrata virulence, which acts by protecting the yeast cells from the overexpression of AMPs, deployed as a host defense mechanism.


Asunto(s)
Candida glabrata/genética , Candidiasis/microbiología , Proteínas Fúngicas/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Poliaminas/farmacología , Proteínas Citotóxicas Formadoras de Poros/farmacología , Antifúngicos/metabolismo , Antifúngicos/farmacología , Candida glabrata/efectos de los fármacos , Candida glabrata/metabolismo , Candida glabrata/patogenicidad , Candidiasis/tratamiento farmacológico , Candidiasis/metabolismo , Farmacorresistencia Fúngica , Proteínas Fúngicas/metabolismo , Regulación Fúngica de la Expresión Génica , Genes Fúngicos , Histatinas/metabolismo , Histatinas/farmacología , Humanos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Poliaminas/metabolismo , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Virulencia
3.
Artículo en Inglés | MEDLINE | ID: mdl-32571817

RESUMEN

The ability to acquire azole resistance is an emblematic trait of the fungal pathogen Candida glabrata Understanding the molecular basis of azole resistance in this pathogen is crucial for designing more suitable therapeutic strategies. This study shows that the C. glabrata transcription factor (TF) CgRpn4 is a determinant of azole drug resistance. RNA sequencing during fluconazole exposure revealed that CgRpn4 regulates the expression of 212 genes, activating 80 genes and repressing, likely in an indirect fashion, 132 genes. Targets comprise several proteasome and ergosterol biosynthesis genes, including ERG1, ERG2, ERG3, and ERG11 The localization of CgRpn4 to the nucleus increases upon fluconazole stress. Consistent with a role in ergosterol and plasma membrane homeostasis, CgRpn4 is required for the maintenance of ergosterol levels upon fluconazole stress, which is associated with a role in the upkeep of cell permeability and decreased intracellular fluconazole accumulation. We provide evidence that CgRpn4 directly regulates ERG11 expression through the TTGCAAA binding motif, reinforcing the relevance of this regulatory network in azole resistance. In summary, CgRpn4 is a new regulator of the ergosterol biosynthesis pathway in C. glabrata, contributing to plasma membrane homeostasis and, thus, decreasing azole drug accumulation.


Asunto(s)
Candida glabrata , Fluconazol , Factores de Transcripción , Antifúngicos/farmacología , Candida glabrata/genética , Candida glabrata/metabolismo , Membrana Celular/metabolismo , Farmacorresistencia Fúngica/genética , Ergosterol , Fluconazol/farmacología , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Regulación Fúngica de la Expresión Génica , Permeabilidad , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
4.
Nucleic Acids Res ; 46(D1): D348-D353, 2018 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-29036684

RESUMEN

The YEAst Search for Transcriptional Regulators And Consensus Tracking (YEASTRACT-www.yeastract.com) information system has been, for 11 years, a key tool for the analysis and prediction of transcription regulatory associations at the gene and genomic levels in Saccharomyces cerevisiae. Since its last update in June 2017, YEASTRACT includes approximately 163000 regulatory associations between transcription factors (TF) and target genes in S. cerevisiae, based on more than 1600 bibliographic references; it also includes 247 specific DNA binding consensus recognized by 113 TFs. This release of the YEASTRACT database provides new visualization tools to visualize each regulatory network in an interactive fashion, enabling the user to select and observe subsets of the network such as: (i) considering only DNA binding evidence or both DNA binding and expression evidence; (ii) considering only either positive or negative regulatory associations; or (iii) considering only one set of related environmental conditions. A further tool to observe TF regulons is also offered, enabling a clear-cut understanding of the exact meaning of the available data. We believe that with this new version, YEASTRACT will improve its role as an open web resource instrumental for Yeast Biologists and Systems Biology researchers.


Asunto(s)
Bases de Datos Genéticas , Regulación Fúngica de la Expresión Génica , Redes Reguladoras de Genes , Saccharomyces cerevisiae/genética , Transcripción Genética , Regulón , Factores de Transcripción/metabolismo
5.
Artículo en Inglés | MEDLINE | ID: mdl-30348666

RESUMEN

Candida glabrata is an emerging fungal pathogen. Its increased prevalence is associated with its ability to rapidly develop antifungal drug resistance, particularly to azoles. In order to unravel new molecular mechanisms behind azole resistance, a transcriptomics analysis of the evolution of a C. glabrata clinical isolate (isolate 044) from azole susceptibility to posaconazole resistance (21st day), clotrimazole resistance (31st day), and fluconazole and voriconazole resistance (45th day), induced by longstanding incubation with fluconazole, was carried out. All the evolved strains were found to accumulate lower concentrations of azole drugs than the parental strain, while the ergosterol concentration remained mostly constant. However, only the population displaying resistance to all azoles was found to have a gain-of-function mutation in the C. glabrataPDR1 gene, leading to the upregulation of genes encoding multidrug resistance transporters. Intermediate strains, exhibiting posaconazole/clotrimazole resistance and increased fluconazole/voriconazole MIC levels, were found to display alternative ways to resist azole drugs. Particularly, posaconazole/clotrimazole resistance after 31 days was correlated with increased expression of adhesin genes. This finding led us to identify the Epa3 adhesin as a new determinant of azole resistance. Besides being required for biofilm formation, Epa3 expression was found to decrease the intracellular accumulation of azole antifungal drugs. Altogether, this work provides a glimpse of the transcriptomics evolution of a C. glabrata population toward multiazole resistance, highlighting the multifactorial nature of the acquisition of azole resistance and pointing out a new player in azole resistance.


Asunto(s)
Antifúngicos/farmacología , Azoles/farmacología , Candida glabrata/efectos de los fármacos , Candida glabrata/genética , Farmacorresistencia Fúngica/genética , Candida glabrata/aislamiento & purificación , Clotrimazol/farmacología , Ergosterol/metabolismo , Fluconazol/farmacología , Regulación Fúngica de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas de Transporte de Membrana/genética , Pruebas de Sensibilidad Microbiana , Factores de Transcripción/genética , Transcriptoma/genética , Triazoles/farmacología , Voriconazol/farmacología
6.
Int J Mol Sci ; 20(9)2019 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-31083555

RESUMEN

Candida albicans and Candida glabrata are the two most prevalent etiologic agents of candidiasis worldwide. Although both are recognized as pathogenic, their choice of virulence traits is highly divergent. Indeed, it appears that these different approaches to fungal virulence may be equally successful in causing human candidiasis. In this review, the virulence mechanisms employed by C. albicans and C. glabrata are analyzed, with emphasis on the differences between the two systems. Pathogenesis features considered in this paper include dimorphic growth, secreted enzymes and signaling molecules, and stress resistance mechanisms. The consequences of these traits in tissue invasion, biofilm formation, immune system evasion, and macrophage escape, in a species dependent manner, are discussed. This review highlights the observation that C. albicans and C. glabrata follow different paths leading to a similar outcome. It also highlights the lack of knowledge on some of the specific mechanisms underlying C. glabrata pathogenesis, which deserve future scrutiny.


Asunto(s)
Candida albicans/patogenicidad , Candida glabrata/patogenicidad , Animales , Biopelículas/crecimiento & desarrollo , Candida albicans/inmunología , Candida albicans/fisiología , Candida glabrata/inmunología , Candida glabrata/fisiología , Interacciones Huésped-Patógeno/inmunología , Humanos , Evasión Inmune , Virulencia/inmunología
7.
Commun Biol ; 5(1): 1118, 2022 10 21.
Artículo en Inglés | MEDLINE | ID: mdl-36271293

RESUMEN

The increasing prevalence of candidosis caused by Candida glabrata is related to its ability to acquire azole resistance. Although azole resistance mechanisms are well known, the mechanisms for azole import into fungal cells have remained obscure. In this work, we have characterized two hexose transporters in C. glabrata and further investigate their role as potential azole importers. Three azole susceptible C. glabrata clinical isolates were evolved towards azole resistance and the acquired resistance phenotype was found to be independent of CgPDR1 or CgERG11 mutations. Through whole-genome sequencing, CgHXT4/6/7 was found to be mutated in the three evolved strains, when compared to their susceptible parents. CgHxt4/6/7 and the 96% identical CgHxt6/7 were found to confer azole susceptibility and increase azole accumulation in C. glabrata cells, strikingly rescuing the susceptibility phenotype imposed by CgPDR1 deletion, while the identified loss-of-function mutation in CgHXT4/6/7, leads to increased azole resistance. In silico docking analysis shows that azoles display a strong predicted affinity for the glucose binding site of CgHxt4/6/7. Altogether, we hypothesize that hexose transporters, such as CgHxt4/6/7 and CgHxt6/7, may constitute a family of azole importers, involved in clinical drug resistance in fungal pathogens, and constituting promising targets for improved antifungal therapy.


Asunto(s)
Azoles , Candida glabrata , Candida glabrata/genética , Azoles/farmacología , Azoles/uso terapéutico , Farmacorresistencia Fúngica/genética , Antifúngicos/farmacología , Glucosa , Evolución Molecular , Hexosas
8.
Nanomaterials (Basel) ; 11(2)2021 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-33494168

RESUMEN

The attachment of bacteria and other microbes to natural and artificial surfaces leads to the development of biofilms, which can further cause nosocomial infections. Thus, an important field of research is the development of new materials capable of preventing the initial adhesion of pathogenic microorganisms. In this work, novel polymer/particle composite materials, based on a polythiourethane (PTU) matrix and either spherical (s-ZnO) or tetrapodal (t-ZnO) shaped ZnO fillers, were developed and characterized with respect to their mechanical, chemical and surface properties. To then evaluate their potential as anti-fouling surfaces, the adhesion of two different pathogenic microorganism species, Staphylococcus aureus and Candida glabrata, was studied using atomic force microscopy (AFM). Our results show that the adhesion of both S. aureus and C. glabrata to PTU and PTU/ZnO is decreased compared to a model surface polydimethylsiloxane (PDMS). It was furthermore found that the amount of both s-ZnO and t-ZnO filler had a direct influence on the adhesion of S. aureus, as increasing amounts of ZnO particles resulted in reduced adhesion of the cells. For both microorganisms, material composites with 5 wt.% of t-ZnO particles showed the greatest potential for anti-fouling with significantly decreased adhesion of cells. Altogether, both pathogens exhibit a reduced capacity to adhere to the newly developed nanomaterials used in this study, thus showing their potential for bio-medical applications.

9.
Commun Biol ; 4(1): 886, 2021 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-34285314

RESUMEN

Candida glabrata is an opportunistic pathogen that adheres to human epithelial mucosa and forms biofilm to cause persistent infections. In this work, Single-cell Force Spectroscopy (SCFS) was used to glimpse at the adhesive properties of C. glabrata as it interacts with clinically relevant surfaces, the first step towards biofilm formation. Following a genetic screening, RNA-sequencing revealed that half of the entire transcriptome of C. glabrata is remodeled upon biofilm formation, around 40% of which under the control of the transcription factors CgEfg1 and CgTec1. Using SCFS, it was possible to observe that CgEfg1, but not CgTec1, is necessary for the initial interaction of C. glabrata cells with both abiotic surfaces and epithelial cells, while both transcription factors orchestrate biofilm maturation. Overall, this study characterizes the network of transcription factors controlling massive transcriptional remodelling occurring from the initial cell-surface interaction to mature biofilm formation.


Asunto(s)
Biopelículas/crecimiento & desarrollo , Candida glabrata/fisiología , Genoma Fúngico , Factores de Transcripción/genética , Candida glabrata/genética , Factores de Transcripción/metabolismo
10.
Artículo en Inglés | MEDLINE | ID: mdl-32117803

RESUMEN

Biofilm formation and drug resistance are two key pathogenesis traits exhibited by Candida glabrata as a human pathogen. Interestingly, specific pathways appear to be in the crossroad between the two phenomena, making them promising targets for drug development. In this study, the 10 multidrug resistance transporters of the Drug:H+ Antiporter family of C. glabrata were screened for a role in biofilm formation. Besides previously identified players in this process, namely CgTpo1_2 and CgQdr2, two others are shown to contribute to biofilm formation: CgDtr1 and CgTpo4. The deletion of each of these genes was found to lead to lower biofilm formation, in both SDB and RPMI media, while their expression was found to increase during biofilm development and to be controlled by the transcription factor CgTec1, a predicted key regulator of biofilm formation. Additionally, the deletion of CgDTR1, CgTPO4, or even CgQDR2 was found to increase plasma membrane potential and lead to decreased expression of adhesin encoding genes, particularly CgALS1 and CgEPA1, during biofilm formation. Although the exact role of these drug transporters in biofilm formation remains elusive, our current model suggests that their control over membrane potential by the transport of charged molecules, may affect the perception of nutrient availability, which in turn may delay the triggering of adhesion and biofilm formation.


Asunto(s)
Candida glabrata , Preparaciones Farmacéuticas , Antifúngicos , Antiportadores/genética , Biopelículas , Candida glabrata/genética , Humanos , Pruebas de Sensibilidad Microbiana
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