Yeast Toxicogenomics: Genome-Wide Responses to Chemical Stresses with Impact in Environmental Health, Pharmacology, and Biotechnology

The emerging transdisciplinary field of Toxicogenomics aims to study the cell response to a given toxicant at the genome, transcriptome, proteome, and metabolome levels. This approach is expected to provide earlier and more sensitive biomarkers of toxicological responses and help in the delineation of regulatory risk assessment. The use of model organisms to gather such genomic information, through the exploitation of Omics and Bioinformatics approaches and tools, together with more focused molecular and cellular biology studies are rapidly increasing our understanding and providing an integrative view on how cells interact with their environment. The use of the model eukaryote Saccharomyces cerevisiae in the field of Toxicogenomics is discussed in this review. Despite the limitations intrinsic to the use of such a simple single cell experimental model, S. cerevisiae appears to be very useful as a first screening tool, limiting the use of animal models. Moreover, it is also one of the most interesting systems to obtain a truly global understanding of the toxicological response and resistance mechanisms, being in the frontline of systems biology research and developments. The impact of the knowledge gathered in the yeast model, through the use of Toxicogenomics approaches, is highlighted here by its use in prediction of toxicological outcomes of exposure to pesticides and pharmaceutical drugs, but also by its impact in biotechnology, namely in the development of more robust crops and in the improvement of yeast strains as cell factories

Genome-scale metabolic model of the human pathogen Candida albicans: a promising platform for drug target prediction

Candida albicans is one of the most impactful fungal pathogens and the most common cause of invasive candidiasis, which is associated with very high mortality rates. With the rise in the frequency of multidrug-resistant clinical isolates, the identification of new drug targets and new drugs is crucial in overcoming the increase in therapeutic failure. In this study, the first validated genome-scale metabolic model for Candida albicans, iRV781, is presented. The model consists of 1221 reactions, 926 metabolites, 781 genes, and four compartments. This model was reconstructed using the open-source software tool merlin 4.0.2. It is provided in the well-established systems biology markup language (SBML) format, thus, being usable in most metabolic engineering platforms, such as OptFlux or COBRA. The model was validated, proving accurate when predicting the capability of utilizing different carbon and nitrogen sources when compared to experimental data. Finally, this genome-scale metabolic reconstruction was tested as a platform for the identification of drug targets, through the comparison between known drug targets and the prediction of gene essentiality in conditions mimicking the human host. Altogether, this model provides a promising platform for global elucidation of the metabolic potential of C. albicans, possibly guiding the identification of new drug targets to tackle human candidiasis.“Fundação para a Ciência e a Tecnologia” (FCT) [Contract PTDC /BII-BIO/28216/2017] and by Programa Operacional Regional de Lisboa 2020 [LISBOA-01-0145-FEDER-022231], through the Biodata.pt Research Infrastructure. Funding received by iBB-Institute for Bioengineering and Biosciences from FCT [Contract UIDB/04565/2020]info:eu-repo/semantics/publishedVersio

Genome-scale metabolic model of the human pathogen C. albicans: aiming the identification of promising new drug targets

Candida albicans is the most common cause of invasive candidiasis, partly due to its ability to acquire drug resistance. With the rise in frequency of multidrug resistant clinical isolates, therapeutic options are running low. The identification of new drug targets and new drugs is crucial to overcome the increase in therapeutic failure. Currently, genome-scale metabolic models can be considered established tools for drug targeting. In this study, we propose the first genome-scale metabolic model for Candida albicans, iRV1930. The model consists of 1556 reactions, 1344 metabolites, 1053 genes, and 5 compartments. This model, currently under validation, proved accurate when predicting the capability of utilizing different carbon and nitrogen sources when compared to experimental data. This model was reconstructed using open source software tool, merlin 3.9.6, and is provided in the well-established systems biology markup language (SBML) format, thus, it can be used in most metabolic engineering platforms, such as OptFlux or Cobra. Altogether, this model provides a promising platform for global elucidation of the metabolism of C. albicans, currently being used to guide the identification of new drug targets to tackle human candidiasis.info:eu-repo/semantics/publishedVersio

Tackling perception and deception in STEM: a critical thinking skill for early-career development

The Universitat Politècnica de Catalunya (UPC), the Instituto Superior Técnico (ISTUniversidade de Lisboa) and the Czech Technical University (CTU) have recently launched the Engine4STEMers project, a joint initiative whose objective, among others, is to guide young graduates in their transition to the job market and motivate them to adopt management and leadership skills early in their careers. In this context, this short paper describes the objectives and contents of a Critical Thinking seminar, currently underway at UPC, which is aimed at motivating young STEM graduates to develop the principles of a skeptical attitude towards the information and stimuli that we perceive in order to face uncertainty, biased information and hidden agendas. Engine4STEMers needs analysis has revealed the importance of a good understanding of the concepts of perception and deception to develop effective interpersonal skills and, more importantly, to ease decision-making processes in a VUCA (volatile, uncertain, complex and ambiguous) environment

Insights into the antimicrobial activities and metabolomes of Aquimarina (Flavobacteriaceae, Bacteroidetes) species from the rare marine biosphere

Two novel natural products, the polyketide cuniculene and the peptide antibiotic aquimarin, were recently discovered from the marine bacterial genus Aquimarina. However, the diversity of the secondary metabolite biosynthetic gene clusters (SM-BGCs) in Aquimarina genomes indicates a far greater biosynthetic potential. In this study, nine representative Aquimarina strains were tested for antimicrobial activity against diverse human-pathogenic and marine microorganisms and subjected to metabolomic and genomic profiling. We found an inhibitory activity of most Aquimarina strains against Candida glabrata and marine Vibrio and Alphaproteobacteria species. Aquimarina sp. Aq135 and Aquimarina muelleri crude extracts showed particularly promising antimicrobial activities, amongst others against methicillin-resistant Staphylococcus aureus. The metabolomic and functional genomic profiles of Aquimarina spp. followed similar patterns and were shaped by phylogeny. SM-BGC and metabolomics networks suggest the presence of novel polyketides and peptides, including cyclic depsipeptide-related compounds. Moreover, exploration of the ‘Sponge Microbiome Project’ dataset revealed that Aquimarina spp. possess low-abundance distributions worldwide across multiple marine biotopes. Our study emphasizes the relevance of this member of the microbial rare biosphere as a promising source of novel natural products. We predict that future metabologenomics studies of Aquimarina species will expand the spectrum of known secondary metabolites and bioactivities from marine ecosystems.info:eu-repo/semantics/publishedVersio

Development of Polythiourethane/ZnO-Based Anti-Fouling Materials and Evaluation of the Adhesion of Staphylococcus aureus and Candida glabrata Using Single-Cell Force Spectroscopy

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

Candida Biofilms: Threats, Challenges, and Promising Strategies

Candida species are fungal pathogens known for their ability to cause superficial and systemic infections in the human host. These pathogens are able to persist inside the host due to the development of pathogenicity and multidrug resistance traits, often leading to the failure of therapeutic strategies. One specific feature of Candida species pathogenicity is their ability to form biofilms, which protects them from external factors such as host immune system defenses and antifungal drugs. This review focuses on the current threats and challenges when dealing with biofilms formed by Candida albicans, Candida glabrata, Candida tropicalis, and Candida parapsilosis, highlighting the differences between the four species. Biofilm characteristics depend on the ability of each species to produce extracellular polymeric substances (EPS) and display dimorphic growth, but also on the biofilm substratum, carbon source availability and other factors. Additionally, the transcriptional control over processes like adhesion, biofilm formation, filamentation, and EPS production displays great complexity and diversity within pathogenic yeasts of the Candida genus. These differences not only have implications in the persistence of colonization and infections but also on antifungal resistance typically found in Candida biofilm cells, potentiated by EPS, that functions as a barrier to drug diffusion, and by the overexpression of drug resistance transporters. The ability to interact with different species in in vivo Candida biofilms is also a key factor to consider when dealing with this problem. Despite many challenges, the most promising strategies that are currently available or under development to limit biofilm formation or to eradicate mature biofilms are discussed

Microbial mechanisms of tolerance to weak acids: an overview

Carboxylic acids are ubiquitous molecules found in microbial metabolic pathways and that have been explored for a wide array of applications including food preservation (e.g., acetic, propionic, benzoic, and sorbic acids), chemotherapy (e.g., the analgesic acetylsalicylic acid, the immunosuppressor mycophenolic acid or the antimalarial drugs artesunic and artemisinic acids) or agriculture (e.g., the herbicides 2,4-dichlorophenoxyacetic acid). This Research Topic contributes to the understanding of the molecular mechanisms underlying adaptation to weak acid stress in microbes, a knowledge base that impacts the fields of Medicine, Health, Food Safety and the Environment