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Mónica da Luz Galocha defended her PhD thesis in Biotechnology and Biosciences, titled “Unveiling new pathways of genomic evolution towards drug resistance in Candida glabrata”, on the 13th of February 2023, at Instituto Superior Técnico. During the previous four years, and under the supervision of Miguel Cacho Teixeira from iBB, Mónica studied the genomic basis of the evolution towards antifungal drug resistance in the fungal pathogen Candida glabrata, uncovering fascinating new mechanisms of azole drug import and transcriptome-wide remodelling in the dependency of mediator complex components.

Mónica Galocha was distinguished with the Best PhD Work in Research and Infectious Diseases by redeSAÚDE, University of Lisbon, at the 6th redeSAÚDE conference held at University of Lisboa on the 15th of November 2022. Mónica Galocha presented her research focused on unveiling new pathways of genomic evolution towards drug resistance in Candida glabrata, carried at iBB, under the supervision of Professor Miguel Cacho Teixeira.

Genome sequencing is a powerful tool that contributes to the advancement of drug resistance studies, population dynamics and evolution in fungal pathogens. In a paper just published in Microbial Cell, emerging from a collaboration between Miguel Cacho Teixeira’s team, iBB, and Hiroji Chibana, MMRC, Japan, the analysis of nearly 100 genomes of globally distributed C. glabrata isolates enabled the identification of new effectors of azole and echinocandin resistance. Their genomic landscape was further explored to evaluate genetic variants specific to each drug resistance profile. Interestingly, the data concludes that changes in the most studied drug resistance genes only occur in a fraction of the resistant isolates, an observation that is expected to contribute to design more suitable antifungal therapeutic strategies.

The marine bacterial genus Aquimarina is a promising source of novel natural products. A new study published in Marine Drugs demonstrated widespread ability of Aquimarina species to inhibit growth of human-pathogenic microbes such as Candida glabrata and methicillin-resistant Staphylococcus aureus, as well as Vibrio and other marine bacteria relevant to aquaculture. Metabolomics and genomics analyses of Aquimarina strains indicated the presence of novel polyketides and peptides, including cyclic depsipeptide-related compounds. The study further showed that Aquimarina species possess low-abundance distributions across marine biotopes worldwide. It emphasizes the relevance of this member of the microbial rare biosphere as a promising source of novel natural products, supporting future efforts to isolate new bioactive compounds from Aquimarina. The work was developed within the SymbioReactor project (DGPM | Fundo Azul program) led by Prof Rodrigo Costa and Dr Tina Keller-Costa and was first-authored by PhD student Sandra Silva. It also includes former MSc student Patrícia Paula, Dr Dalila Mil-Homens, Prof Miguel Teixeira and Prof Arsénio Fialho from BSRG-iBB as coauthors.

The prevalence of antifungal resistance in Candida glabrata, especially against azole drugs, results in difficult-to-treat and potentially life-threatening infections. In this study, the role of a newly described transcription factor, Mar1, in azole susceptibility was explored. Using RNA-sequencing, its role in the transcriptome-wide response to fluconazole is assessed, leading to the elucidation of its role in modulating azole susceptibility, dependent on membrane sphingolipid incorporation, membrane permeability, and intracellular drug accumulation. Altogether, a regulatory pathway modulating azole susceptibility in C. glabrata is proposed, resulting from what appears to be a neofunctionalization of a Hap1-like transcription factor. These results obtained by an international team led by Miguel Cacho Teixeira, BSRG-iBB, just published in Journal of Fungi, are expected to contribute to maintain the usability of this drug in antifungal therapy.

Cellular components that contribute to both pathogenesis and drug resistance are among the most promising drug targets in human pathogens. In this study, the uncharacterized drug:H+ antiporter CgTpo4 was shown to play a role in Candida glabrata virulence in the infection model G. mellonella. The underlying mechanism was demonstrated to include a role in AntiMicrobial Peptide (AMP) resistance, compatible with the observed immune response deployed by G. mellonella upon C. glabrata infection. These results, emerging from a collaboration between BSRG members, led by Miguel Cacho Teixeira and including Arsénio Fialho and Dalila Mil-Homens, were just published in International Journal of Molecular Sciences and are expected to contribute to design more suitable antifungal therapeutic strategies.

Saccharomyces boulardii has been widely used, for more than 50 years, as a human probiotic. Nonetheless, the molecular basis underlying its mode of action is scarcely understood. In this study, global gene expression analysis, resorting to Illumina- based RNA-sequencing, was conducted to analyze differential gene expression patterns in S. cerevisiae and S. cerevisiae var. boulardii in GI- tract like medium. Additionally, based on the construction of an S. cerevisiae var. boulardii database, a global comparison between gene promoter sequences in S. cerevisiae and S. cerevisiae var. boulardii strains was conducted. The obtained results shed light into the molecular basis of the differential probiotic phenotypes displayed by these two closely related yeasts. The knowledge gathered through this study, by a team led by Miguel Cacho Teixeira, BSRG-iBB, and Pedro T Monteiro, INESC-ID, and just published in Genomics, is expected to contribute to guide the design of more rationale, probiotic-based, therapeutic approaches.

Understanding the rules that govern complex transcriptional regulation has been attempted for many years. In this study, the full network of transcriptional regulatory associations currently known for Saccharomyces cerevisiae, as gathered in the latest release of the YEASTRACT database, was topologically evaluated. Overall, our analyses challenge previous results, pointing out towards the paucity of experimental evidence to support theories. This study, that stems from a collaboration between researchers from BSRG/iBB (Miguel Cacho Teixeira), INESC-ID (Pedro Monteiro) and IGC (Claudine Chaouiya), was just published in Scientific Reports.

The YEASTRACT+ information system (http://YEASTRACT-PLUS.org/) is a wide-scope computational tool for the analysis and prediction of transcription regulatory associations at the gene and genomic levels in 10 yeast species of biotechnological or human health relevance. A large team led by Isabel Sá-Correia, Miguel Teixeira, from iBB, and Pedro Monteiro, from INESC-ID, has just released this new web-portal in the 2020 Nucleic Acids Research Database Issue and is compromised to continue its efforts to expand this resource, which is currently supported within the context of the Biodata.pt/Elixir.pt Research Infrastructure.

Marine microbiomes are prolific sources of bioactive compounds of pharmaceutical value. A new study, published in Marine Drugs, inspected two culture collections comprising 919 host-associated marine bacteria belonging to 55 genera and several unclassified lineages. The study identified numerous isolates with a potentially rich secondary metabolism and inhibitory activities towards human-pathogenic bacteria and fungi. These culture collections, available at iBB-IST and Aveiro University, are a valuable resource of understudied marine bacteria that hold promise for a future, sustainable production of novel drug leads. The work was developed within the SymbioReactor project (DGPM | Fundo Azul program), first-authored by MSc João Almeida and coordinated by Dr Tina Keller-Costa and Prof Rodrigo Costa. The study also involved PhD student Matilde Marques, Dr Dalila Mil-Homens, Prof Miguel Teixeira and Prof Arsénio Fialho from iBB as well collaborators from Aveiro University and Biocant.

The YEASTRACT+ information system is a wide-scope computational tool for the analysis and prediction of transcription regulatory associations at the gene and genomic levels in 11 yeast species of biotechnological or human health relevance. Its newest release, orchestrated by a large team led by Isabel Sá-Correia, Miguel Teixeira, from iBB, and Pedro Monteiro, from INESC-ID, has just described in the 2023 Nucleic Acids Research Database Issue, highlighting the availability of new regulatory-metabolic network modeling tools. These tools are expected to contribute to guide YEASTRACT+ users in the optimization of yeast cell factories of industrial relevance and the identification of new antifungal drug targets, to be used in advanced antifungal therapy. YEASTRACT+ is currently supported within the context of the Biodata.pt/Elixir.pt Research Infrastructure.

Following the genomic alterations occurring in a cell population as it evolves towards drug resistance in C. glabrata is a promising way of identifying the drug resistance mechanisms that actually take place in the clinical setting. In a recent study, lead by Miguel Cacho Teixeira’s (BSRG-iBB) and Acácio Rodrigues’ (CINTESIS-FMUP) teams, together with Patrick Van Dijck (UCL, Louvain, Belgium), Hiroji Chibana (MMRC, Chiba Univ, Japan) and Cláudio Soares (ITQB-NOVA), the genomic changes underlying Posaconazole resistance acquisition in C. glabrata were evaluated. Based on the obtained results, the hexose transporters Hxt4/6/7 and Hxt6/7 were identified and determinants of azole susceptibility and proposed to act as azole importers. These results, recently published in Communications Biology, are believed to be just the tip of the iceberg, as many other hexose transporter family members may play similar roles in all fungal pathogens.

Miguel Cacho Teixeira’s was recognized in this year’s edition of the ULisboa/CGD scientific prizes. Miguel received an honorable mention for his work in the category "Biology, Biological Engineering, Biochemistry and Biotechnology". His work is focused on understanding fungal infections caused by pathogenic yeasts of the Candida genus, on a genome-wide perspective, and on using this information to improve therapeutic options. The award ceremony took place on the 28th of June.

Understanding the behavior of human pathogens is both a challenge and a need, if we are to address infectious diseases with the best possible tools. Genome-scale metabolic models are a way to meet this task, which was just used for the second most prevalent Candida species in Europe, Candida parapsilosis. The construction and validation of a global stoichiometric model describing the whole metabolic network in this human pathogen, as well as its exploitation in drug target discovery, stemming from a collaboration between researchers from BSRG/iBB (Miguel Cacho Teixeira), ITQB-NOVA (Isabel Rocha) and CEB-UMinho (Óscar Dias), was just published in Genes.

Responding to the recent interest of the yeast research community in non-Saccharomyces cerevisiae species of biotechnological relevance, the N.C.Yeastract was associated to YEASTRACT+, a curated repository of known regulatory associations between transcription factors (TFs) and target genes in yeasts. A recent Minireview published in FEMS Yeast Research aims to advertise the update of the existing information since the release of N.C.Yeastract in 2019, and to raise awareness in the community about its potential to help the day-to-day work on non-Saccharomyces species, exploring all the information and bioinformatics tools available in YEASTRACT +. Using simple and widely used examples, a guided exploitation is offered. The usage potentialities of the new CommunityYeastract platform by the yeast community are also discussed. The Minireview is coauthored by a BSRG-iBB team coordinated by Isabel Sá-Correia and including Cláudia P. Godinho, Margarida Palma, Miguel C. Teixeira and the PhD students Miguel Antunes and Marta N. Mota, in collaboration with INESC-ID colleagues.

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 were developed and characterized with respect to their mechanical, chemical and surface properties. Both S. aureus and C. glabrata exhibit a reduced capacity to adhere to the newly developed nanomaterials used in this study, thus showing their potential for bio-medical applications. This study, led by researchers from LAAS-CNRS, Toulouse, and co-authored by Mafalda Cavalheiro and Miguel Cacho Teixeira from BSRG-iBB, was just published in Nanomaterials.

Candida glabrata’s ability to cause persistent human infections is tightly linked to its impressive ability to overcome host immune system defenses. The molecular basis of virulence in this pathogen are far from being clarified, as it lacks many of the typical pathogenesis features displayed by other Candida species. In this study, the transcription factor Tog1 was found to play a key role in the transcriptome-wide response to oxidative stress, enabling higher proliferation upon phagocytosis and increased virulence. The knowledge gathered through this study, by an international team led by Miguel Cacho Teixeira, BSRG-iBB, and just published in Virulence, is expected to contribute to guide the design of more successful therapeutic approaches.

New drugs are highly needed to treat human candidiasis. The ability to find interesting new drug targets is now expanded by the construction and validation of a global stoichiometric model describing the whole metabolic network in the human pathogen Candida albicans. This application of Systems Biology to tackle pathogenesis is highly innovative, and stems from a collaboration between researchers from BSRG/iBB (Miguel Cacho Teixeira), ITQB-NOVA (Isabel Rocha) and CEB-UMinho (Óscar Dias). The description of this model and of its potential have just been published in Journal of Fungi.

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 to design more suitable therapeutic strategies. In this study, the transcription factor Rpn4 was found to play a key role in the transcriptome-wide response to fluconazole. Rpn4 is described a new regulator of the ergosterol biosynthesis pathway in C. glabrata, contributing to plasma membrane homeostasis, decreasing azole drug accumulation and, thus, conferring azole resistance. These results  obtained by an international team led by Miguel Cacho Teixeira, BSRG-iBB, just published in Antimicrobial Agents and Chemotherapy, are expected to contribute to maintain the usability of this drug in antifungal therapy.