Drug: Proton antiporters in chemical stress defense

Team :   Isabel Sá-Correia, Miguel C Teixeira, Nuno P Mira, Paulo J Dias, Sandra C dos Santos, Catarina P Costa.


Multidrug resistance (MDR) is implicated in the failure of many therapeutic, food-preservation and crop protection actions, but can be used to good effect in the improvement of biotechnological processes' productivity. MDR is many times the result of the action of multidrug efflux transporters found in the plasma membrane of all living cells.


Research Topics

The emergence of multidrug resistance (MDR), i.e. the simultaneous acquisition of resistance to a wide range of structurally and functionally unrelated cytotoxic chemicals is found in a wide variety of organisms, from bacteria to mammals. This phenomenon is many times dependent on the action of drug efflux pumps that apparently mediate the expulsion of drugs and other cytotoxic compounds from the cytoplasm to the outer medium, providing protection from their toxic effects.


1.   Functional analysis of new MDR transporters of the MFS in S. cerevisiae

The yeast S. cerevisiae has a privileged position as a tool for the understanding of mechanisms underlying cytotoxic insults in more complex and less easily accessible eukaryotes. Since the release of the yeast genome sequence, our research group has been involved in the functional analysis of new MDR transporters of the Major Facilitator Superfamily (MFS-MDR). The ongoing research pursues a deeper understanding of the physiological role of these drug-H + antiporters, (12- and 14- spanner drug:H +antiporter DHA1 and DHA2 families) their contribution to MDR resistance, the complex transcription networks involved in their regulation in response to drugs/chemical stress, their evolution and on how this knowledge can be extrapolated to pathogenic fungi and higher eukaryotes.

2. Extrapolation of the current knowledge on MDR transporters to pathogenic and phytopathogenic yeasts and to the plant model Arabidopsis thaliana

The use of S. cerevisiae as a model system to study agricultural and clinical antifungal resistance has provided promising clues to guide the study of antifungal resistance in pathogenic and phytopathogenic yeasts. In particular, this knowledge and experimental approaches are being used to guide the functional characterization of a family of drug:H + antiporters in the pathogenic yeast Candida glabrata.

The role of S. cerevisiae drug efflux pumps in resistance to the herbicide 2,4-D has been characterized by our group over the last years. The implications of this knowledge in A. thaliana resistance to herbicides and other pesticides and phytotoxics, and the use of yeast as a heterologous expression system, are being examined, in collaboration with the Plant Molecular Biology group, Instituto Gulbenkian de Ciência. A new family of putative MDR transporters of the Major Facilitator Superfamily in A. thaliana is also being characterized as a result of this joint effort aiming the development of herbicide-resistant crops.



Selected Publications

- Remy, E., Cabrito, T.R., Batista, R.A., Hussein, M.A.M., Teixeira, M.C., Athanasiadis, A., Sá-Correia, I., Duque, P., "Intron Retention in the 5'UTR of the Novel ZIF2 Transporter Enhances Translation to Promote Zinc Tolerance in Arabidopsis", PLoS Genetics, 10(5):e1004375, 2014.

- 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.

- dos Santos, S.C., Teixeira, M.C., Dias, P.J., Sá-Correia, I., MFS transporters required for multidrug/multixenobiotic (MD/MX) resistance in the model yeast: understanding their physiological function through post-genomic approaches, Frontiers in Physiology, 5:180, 2014.

- 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.

- Dias P.J., Sá-Correia I., "Phylogenetic and syntenic analyses of the 12-spanner drug:H(+) antiporter family 1 (DHA1) in pathogenic Candida species: evolution of MDR1 and FLU1 genes". Genomics, 104(1):45-57, 2014.

- Costa, C., Pires, C., Cabrito, T.R., Renaudin, A., Ohno, M., Chibana, H., Sá-Correia, I., Teixeira, M.C., 2013, 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.

- Dias, P.J., Sá-Correia, I., The drug:H+ antiporters of family 2 (DHA2), siderophore transporters (ARN) and glutathione:H+ antiporters (GEX) have a common evolutionary origin in hemiascomycete yeasts, BMC Genomics, 14: 901, 2013.

- Remy, E., Cabrito, T.R., Baster, P., Batista, R.A., Teixeira, M.C., Friml, J., Sá-Correia, I., Duque, P., 2013, A Major Facilitator Superfamily Transporter Plays a Dual Role in Polar Auxin Transport and Drought Stress Tolerance in Arabidopsis, The Plant Cell, 25: 901-26.

- Sá-Correia, I., dos Santos, S.C., Teixeira, M.C., Cabrito, T.R., Mira, N.P., "Drug:H+ antiporters in chemical stress response in yeast".Trends in Microbiology , 17, 22-31, 2009.