Fungal Pathogenesis and Drug Resistance: a molecular systems approach

The FunPath Lab 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.

FunPath is one of the Labs hosted by the Biological Sciences Research Group of iBB - Institute for Bioengineering and Biosciences of Instituto Superior Técnico. 

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 FunPath Lab, particular focus is being 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 defenses.

Our current projects within this subject include:

-     The use of genomics [1,2], transcriptomics [3], proteomics [4] and chemogenomics to unravel the evolution of C. glabrata clinical isolates towards clinically-relevant phenotypes.

-        The development of computational tools [5,6] and models [7] to study transcriptional regulation and metabolism in C. glabrata, C. albicans and C. parapsilosis at a genomic scale, including particularly the PathoYeastract database.

-          The characterization of the large array of multidrug resistance transporters, particularly those belonging to the Major Facilitator Superfamily, encoded by the genome sequence of Candida glabrata. These transporters have been shown to confer antifungal drug resistance [8,9], but surprisingly, also increased virulence [10] and biofilm formation [11]. 

-         The characterization of the transcription regulatory networks controlling C. glabrata response to clinically-relevant stresses and conditions [12,13,14].

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 determinants of biofilm formation, drug resistance or virulence; iii) the design of more effective drugs, to be used alone or in combination therapy with currently existing antifungals.

[1] Galocha, M., Viana, R., Pais, P., Silva-Dias, A., Cavalheiro, M., Miranda, I.M., Van Ende, M., Souza, C.S., Costa, C., Branco, J., Soares, C.M., Van Dijck, P., Rodrigues, A.G.**, Teixeira, M.C.**, “Genomic evolution towards azole resistance in Candida glabrata clinical isolates unveils the importance of CgHxt4/6/7 in azole accumulation”, Communications Biology, 5: 1118, 2022.

[2] Pais, P.*, Galocha, M.*, Takahashi-Nakaguchi, A., Chibana, H., Teixeira, M.C., “Multiple genome analysis of Candida glabrata clinical isolates renders new insights into genetic diversity and drug resistance determinants”, Microbial Cell, 9(11): 174-189, 2022.

[3] Cavalheiro, M., Costa, C., Silva-Dias, A., Miranda, I.M., Wang, C., Pais, P., Pinto, S.N., Mil-Homens, D., Sato-Okamoto, M., Takahashi-Nakaguchi, A., Silva, R.M., Mira, N.P., Fialho, A.M., Chibana, H., Rodrigues, A.G., Butler, G., Teixeira, M.C., 2019, “Unveiling the mechanisms of in vitro evolution towards fluconazole resistance of a Candida glabrata clinical isolate: a transcriptomics approach”, Antimicrobial Agents and Chemotherapy, 63: e00995-18, 2019. 

[4] 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.

[5] 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.

[6] Teixeira, M.C.**, Viana, R., Palma, M., Oliveira, J., Galocha, M., Mota, M.N., Couceiro, D., Pereira, M.G., Antunes, M., Costa, I.V., Pais, P., Parada, C., Chaouiya, C., Sá-Correia, I.**, Monteiro, P.T.**, “YEASTRACT+: a portal for the exploitation of global transcription regulation and metabolic model data in yeast biotechnology and pathogenesis”, Nucleic Acids Research, 51(D1):D785-D791, 2023.

[7] Viana, R., Dias, O., Lagoa, D., Galocha, M., Rocha, I.**, Teixeira, M.C.**, “Genome-scale metabolic model of the human pathogen Candida albicans: a platform for drug target prediction”, Journal of Fungi, 6: 171, 2020.

[8] 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.

[9] 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.

[10] 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.,  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, 2017.

[11] Santos, R.*, Cavalheiro, M.*, Costa, C., Takahashi-Nakaguchi, A., Okamoto, M., Chibana, H., Teixeira, M.C., “Screening the Drug:H+ Antiporter family for a role in biofilm formation in Candida glabrata”, Frontiers in Cellular and Infection Microbiology, 10: 29, 2020.

[12] Pais, P., California, R., Galocha, M., Viana, R., Ola, M., Cavalheiro, M., Takahashi-Nakaguchi, A., Chibana, H., Butler, G., Teixeira, M.C., “Candida glabrata transcription factor Rpn4 mediates fluconazole resistance through regulation of ergosterol biosynthesis and plasma membrane permeability”, Antimicrobial Agents and Chemotherapy, 64: e00554-20, 2020.

[13] Pais, P., Vagueiro, S., Mil-Homens, D., Pimenta, A.I., Viana, R., Okamoto, M., Chibana, H., Fialho, A.M., Teixeira, M.C., “A new regulator in the crossroads of oxidative stress resistance and virulence in Candida glabrata: the transcription factor CgTog1”, Virulence, 11(1):1522-1538, 2020.

[14] Cavalheiro, M., Pereira, D., Formosa-Dague, C., Leitão, C., Pais, P., Ndlovu, E., Viana, R., Pimenta, A.I., Santos, R., Takahashi-Nakaguchi, A., Michiyo Okamoto , Mihaela Ola , Chibana, H., Fialho, A.M., Butler, G., Dague, E., Teixeira, M.C., “From the first touch to biofilm establishment by the human pathogen Candida glabrata: a genome-wide to nanoscale view”, Communications Biology, 4: 886, 2021.

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”, 2015-2018.

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.