Theme Leader: Miguel Cacho Teixeira

Infections caused by fungal pathogens have become a relevant threat to human health as their prevalence has continuously increased over the last few decades. As secondary pathogens, they target mostly the growing immunocompromised human population, being able to cause recalcitrant superficial infections and deadly disseminated infections.

At the BSRG, particular focus has been given to fungal infections caused by pathogenic yeasts of the Candida genus, especially C. glabrata. The ability of these species to become effective pathogenic agents relate to their concerted ability to display antifungal drug resistance, virulence factors, and a surprisingly high tolerance to the host’s immune system defences.

Our current projects within this subject include

  • The characterization of the large array of multidrug resistance transporters, particularly those belonging to the Major Facilitator Superfamily [1], encoded by the genome sequence of Candida glabrata.These transporters have been shown to confer antifungal drug resistance [2,3], but surprisingly, also increased virulence [4].
  • The characterization of the transcription regulatory networks controlling glabrata response to clinically-relevant stresses and conditions [5].
  • The development of computational tools and models to study transcriptional regulation in glabrata and C. albicans at a genomic scale, including particularly the PathoYeastract database [6].
  • The use of MS-based proteomics [5], RNA-seq based transcriptomics and chemogenomics to fully unravel the responses displayed by glabrata to clinically-relevant stresses and the underlying signalling pathways.

Altogether, the gathered knowledge is expected to aid in the design of novel tools for: i) the diagnosis of drug resistance in clinical isolates; ii) identification of new drug targets that may act as drug resistance or virulence source; iii) the design of more effective drugs, to be used alone or in combination therapy with currently existing antifungals.

Publications

[1] Costa, C., Dias, P.J., Sá-Correia, I., Teixeira, M.C., “MFS multidrug transporters in pathogenic fungi: do they have real clinical impact?", Frontiers in Physiology, 5:197, 2014.

[2] Costa, C., Nunes, J., Henriques, A., Mira, N.P., Nakayama, H., Chibana, H., Teixeira, M.C., The Candida glabrata drug:H+ antiporter CgTpo3 (ORF CAGL0I10384g): role in azole drug resistance and polyamine homeostasis, Journal of Antimicrobial Chemotherapy, 69:1767-76, 2014.

[3] Costa, C., Pires, C., Cabrito, T.R., Renaudin, A., Ohno, M., Chibana, H., Sá-Correia, I., Teixeira, M.C., “Candida glabrata drug: H+ antiporter CgQdr2 (ORF CAGL0G08624g) confers imidazole drug resistance, being activated by the CgPdr1 transcription factor", Antimicrobial Agents and Chemotherapy, 57(7), 3159-67, 2013.

[4] Santos, R., Costa, C., Mil-Homens, D., Romão, D., de Carvalho, C.C.R., Pais, P., Mira, N.P., Fialho, A.M., Teixeira, M.C., 2017, The multidrug resistance transporters CgTpo1_1 and CgTpo1_2 play a role in virulence and biofilm formation in the human pathogen Candida glabrata“, Cellular Microbiology, 19(5): e12686.

[5] Pais, P., Costa, C., Pires, C., Shimizu, K., Chibana, H., Teixeira, M.C., “Membrane proteome-wide response to the antifungal drug clotrimazole in Candida glabrata: role of the transcription factor CgPdr1 and the Drug:H+ Antiporters CgTpo1_1 and CgTpo1_2”, Molecular and Cellular Proteomics, 15(1):57-72, 2016.

[6] Monteiro, P.T., Pais, P., Costa, C., Manna, S., Sá-Correia, I., Teixeira, M.C., “The PathoYeastract database: an information system for the analysis of gene and genomic transcription regulation in pathogenic yeasts", Nucleic Acids Research, 45(D1):D597-D603, 2017.

External Collaborators

Acácio Rodrigues and Isabel Miranda, Faculdade de Medicina da Universidade do Porto, Portugal.

Hiroji Chibana, Medical Mycology Research Centre, Chiba University, Japan.

Geraldine Butler, University College Dublin, Ireland.

Pedro Monteiro, INESC-ID/IST, Lisboa, Portugal.

Claudine Chaouyia, Instituto Gulbenkian Ciencia, Oeiras, Portugal.

Projects

PTDC/BII-BIO/28216/2017: “MIXED-UP – Targeting pathogenesis and engineering cell factories: by developing mixed regulatory-metabolic genomic models in yeasts", ongoing.

MMRC Joint Usage/Research Project: “Antifungal drug resistance in Candida glabrata from transcriptional control to drug extrusion: aiming improved diagnosis and therapeutics” (partners: iBB-IST, Portugal and MMRC – Medical Mycology Research Center, Chiba University, Japan), ongoing.

PTDC/BBB-BIO/4004/2014: “CANTROL – Deciphering the mechanisms of transcriptional regulation that control antifungal drug resistance in the pathogenic yeast Candida glabrata: aiming the development of improved diagnosis and therapeutic approaches”, ongoing.

BBI8-UID/BIO/04565/2013: “Understanding and exploiting yeast membrane transport in chemotherapy, industrial biotechnology and in plant biology and biotechnology”, 2015-2016.

PTDC/EBB-BIO/119356/2010: “FUNDRING – Identification of new biomarkers of antiFUNgal Drug Resistance diagnosis IN Candida Glabrata: the particular role of multidrug resistance transporters"2012-2015.