MFS transporters required for multidrug/multixenobiotic (MD/MX) resistance in the model yeast: understanding their physiological function through post-genomic approaches

Abstract

Multidrug/Multixenobiotic resistance (MDR/MXR) is a widespread phenomenon with clinical, agricultural and biotechnological implications, where MDR/MXR transporters that are presumably able to catalyze the efflux of multiple cytotoxic compounds play a key role in the acquisition of resistance. However, although these proteins have been traditionally considered drug exporters, the physiological function of MDR/MXR transporters and the exact mechanism of their involvement in resistance to cytotoxic compounds are still open to debate. In fact, the wide range of structurally and functionally unrelated substrates that these transporters are presumably able to export has puzzled researchers for years. The discussion has now shifted toward the possibility of at least some MDR/MXR transporters exerting their effect as the result of a natural physiological role in the cell, rather than through the direct export of cytotoxic compounds, while the hypothesis that MDR/MXR transporters may have evolved in nature for other purposes than conferring chemoprotection has been gaining momentum in recent years. This review focuses on the drug transporters of the Major Facilitator Superfamily (MFS; drug:H+ antiporters) in the model yeast Saccharomyces cerevisiae. New insights into the natural roles of these transporters are described and discussed, focusing on the knowledge obtained or suggested by post-genomic research. The new information reviewed here provides clues into the unexpectedly complex roles of these transporters, including a proposed indirect regulation of the stress response machinery and control of membrane potential and/or internal pH, with a special emphasis on a genome-wide view of the regulation and evolution of MDR/MXR-MFS transporters.

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

“…These observations seem to imply that CgTpo1_1 and CgTpo1_2 are gifted with extraordinary substrate variety, even within their own DHA1 family (7). Consistent with these results, their S. cerevisiae homolog was demonstrated to confer resistance to at least, five different drugs besides polyamines, including the fungicide cycloheximide, the antiarrythmic drug quinidine, the polyene nystatin, and the herbicides 2-methyl-4-chlorophenoxyacetic acid and 2,4-dichlorophenoxyacetic acid (16,17).…”

“…The primary physiological role attributed to Tpo1 has been the transport of polyamines (18), particularly spermidine (19). However, Tpo1 has been shown to confer resistance to numerous chemical stress agents, from herbicides (20) and agricultural fungicides (21) to the antifungal drug caspofungin (22), among many others (16,17). Interestingly, the Tpo1 homolog in C. albicans, CaFlu1, was found to complement fluconazole hypersusceptibility in a S. cerevisiae ⌬pdr5 mutant but not to have a significant role in fluconazole resistance in C. albicans (23).…”

“…S. cerevisiae Tpo1 is one of the best characterized of the eukaryotic Drug:Hϩ Antiporters (16,17). The primary physiological role attributed to Tpo1 has been the transport of polyamines (18), particularly spermidine (19).…”

Structural Biology of the Major Facilitator Superfamily Transporters

“…The MFS transporters involved in the multidrug resistance in bacteria and fungi also have the potential for use in the development of new drugs against pathogenic microorganisms. Multidrug resistance and potential uses of MFS transporters from bacteria and fungi have been covered in recent reviews (10,16).…”

Yeast Fex1p Is a Constitutively Expressed Fluoride Channel with Functional Asymmetry of Its Two Homologous Domains

“…Alternatively, FEX might be modulated by toxin-sensing transcriptional regulators, as for the arsenate transporter protein in Saccharomyces, ScAcr3 (20). Post-transcriptional regulation is also possible, either at the level of translation, such as for the multidrug resistance transporter, ScHol1 (21,22), or at the level of directed targeting, as for the cadmium exporter ScPca1 (23)(24)(25). An additional question exists as to whether limited resistance to fluoride might be gained by shunting this anion to the yeast vacuole, a mechanism of detoxification for several metals (20).…”