Research Topic

Physiological role and regulation of Multidrug/Multixenobiotic resistance membrane transporters

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Multidrug/Multixenobiotic resistance (MDR/MXR) is a widespread phenomenon. Cellular resistance to multiple drugs and other cytotoxic compounds is implicated in the failure of many anticancer, antimicrobial, food-preservation and crop protection actions, is involved in the defense of plants and aquatic ...

Multidrug/Multixenobiotic resistance (MDR/MXR) is a widespread phenomenon. Cellular resistance to multiple drugs and other cytotoxic compounds is implicated in the failure of many anticancer, antimicrobial, food-preservation and crop protection actions, is involved in the defense of plants and aquatic organisms against natural toxins or anthropogenic contaminants and contributes to the productivity improvement of biotechnological processes. MDR/MXR often results from the activity of membrane proteins that are thought to actively export the cytotoxic compounds from cells (the pump action), maintaining the intracellular drug/xenobiotic concentration below the toxic level. Several MDR transporters have been identified and studied in bacteria, fungi, plants, animals and humans, especially those belonging to the ATP-binding cassette (ABC) superfamily, of which the human p-glycoprotein is a paradigmatic case. A less well characterized group of transporters involved in MDR, and proposed to act as Drug:H+ Antiporters (DHA), belong to the major facilitator superfamily (MFS). Although the DHA family of proteins is thought to exist exclusively in bacteria and fungi, based on sequence homology, recent reports have began to show that there are also MFS transporters in complex eukaryotes, including plants, fish and mammals, that confer multiple drug/xenobiotic resistance. MDR/MXR transporters apparently have broad substrate specificities and may transport essential compounds and metabolites in addition to toxins. A complete understanding of the mode of action of these transporters appears thus to be crucial to devise clear cut approaches to overcome clinical multidrug resistance, to enhance multixenobiotic tolerance in biotechnological processes and to decrease the toxicological impact of xenobiotics in ecosystems.
This Research Topic proposes to put together the most recent advances in the field of multidrug/multixenobiotic resistance mediated by membrane transporters. A wide spectrum of perspectives are welcome, including those focused on: 1) the structure, topology, evolution and function of these transporters; 2) the mechanisms behind their apparent promiscuity; 3) the coordination between their physiological role and their action in conferring broad chemoprotection against compounds that are not usually present in their natural environment; 4) the mechanisms of transcriptional and post-translational control of their activity. Studies focused on S. cerevisiae, and other experimental models are welcome given the degree of understanding that can be achieved in these working models. Studies focusing on humans and organisms with impact in human health (including pathogenic bacteria, fungi and parasites), agriculture (such as weeds, crops, and other plants of economical relevance), biotechnology (including microbes or cell lines used as cell factories) and ecotoxicology will also be very much appreciated.
Current and expected impact of this knowledge will also be considered, including in: 1) human health, in particular in antitumor chemotherapy and antimicrobial resistance, from drug resistance diagnosis, to the use of chemosensitizers able to specifically inhibit these transporters; 2) plant defense against other stresses of agricultural relevance and in the use of agricultural pesticides; 3) the use of biological systems to produce and accumulate toxic metabolites or degrade environmental pollutants; 4) ecotoxicity.


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