Multiple molecular mechanisms for multidrug resistance transporters

The acquisition of multidrug resistance is a serious impediment to improved healthcare. Multidrug resistance is most frequently due to active transporters that pump a broad spectrum of chemically distinct, cytotoxic molecules out of cells, including antibiotics, antimalarials, herbicides and cancer...

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Published in	Nature Vol. 446; no. 7137; pp. 749 - 757
Main Author	Higgins, Christopher F
Format	Journal Article
Language	English
Published	London Nature Publishing Group UK 12.04.2007 Nature Publishing Nature Publishing Group
Subjects	Animals Antibacterial agents Antibiotics Antibiotics. Antiinfectious agents. Antiparasitic agents Antiparasitic agents ATP-Binding Cassette Transporters - chemistry ATP-Binding Cassette Transporters - metabolism Biochemistry Biological and medical sciences Biomedical research Chemical compounds Drug resistance Drug Resistance, Multiple - physiology Glycoprotein Health care Herbicides Human Humanities and Social Sciences Humans Mammals Marketing Medical sciences Molecular biology multidisciplinary Multidrug Resistance-Associated Proteins - chemistry Multidrug Resistance-Associated Proteins - metabolism Organisms Pharmacology. Drug treatments Protein Conformation Proteins Pumps review-article Science Science (multidisciplinary) Structure-Activity Relationship Transcription Factors - metabolism Antineoplastic agent Antimalarial Antibiotic Three dimensional structure Molecular structure Multiple resistance Pesticides P Glycoprotein Parasiticide Mechanism of action ABC transporter Herbicide
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Abstract	The acquisition of multidrug resistance is a serious impediment to improved healthcare. Multidrug resistance is most frequently due to active transporters that pump a broad spectrum of chemically distinct, cytotoxic molecules out of cells, including antibiotics, antimalarials, herbicides and cancer chemotherapeutics in humans. The paradigm multidrug transporter, mammalian P-glycoprotein, was identified 30 years ago. Nonetheless, success in overcoming or circumventing multidrug resistance in a clinical setting has been modest. Recent structural and biochemical data for several multidrug transporters now provide mechanistic insights into how they work. Organisms have evolved several elegant solutions to ridding the cell of such cytotoxic compounds. Answers are emerging to questions such as how multispecificity for different drugs is achieved, why multidrug resistance arises so readily, and what chance there is of devising a clinical solution.
AbstractList	The acquisition of multidrug resistance is a serious impediment to improved healthcare. Multidrug resistance is most frequently due to active transporters that pump a broad spectrum of chemically distinct, cytotoxic molecules out of cells, including antibiotics, antimalarials, herbicides and cancer chemotherapeutics in humans. The paradigm multidrug transporter, mammalian P- glycoprotein, was identified 30 years ago. Nonetheless, success in overcoming or circumventing multidrug resistance in a clinical setting has been modest. Recent structural and biochemical data for several multidrug transporters now provide mechanistic insights into how they work. Organisms have evolved several elegant solutions to ridding the cell of such cytotoxic compounds. Answers are emerging to questions such as how multispecificity for different drugs is achieved, why multidrug resistance arises so readily, and what chance there is of devising a clinical solution. The acquisition of multidrug resistance is a serious impediment to improved healthcare. Multidrug resistance is most frequently due to active transporters that pump a broad spectrum of chemically distinct, cytotoxic molecules out of cells, including antibiotics, antimalarials, herbicides and cancer chemotherapeutics in humans. The paradigm multidrug transporter, mammalian P-glycoprotein, was identified 30 years ago. Nonetheless, success in overcoming or circumventing multidrug resistance in a clinical setting has been modest. Recent structural and biochemical data for several multidrug transporters now provide mechanistic insights into how they work. Organisms have evolved several elegant solutions to ridding the cell of such cytotoxic compounds. Answers are emerging to questions such as how multispecificity for different drugs is achieved, why multidrug resistance arises so readily, and what chance there is of devising a clinical solution. [PUBLICATION ABSTRACT] Multidrug resistance Most multidrug resistance mechanisms, for agents as diverse as antibiotics, antifungals, antimalarials, herbicides, and also for cancer chemotherapeutics in man, involve a transporter that pumps the drugs out of the cell. The archetypal such transporter, mammalian P-glycoprotein, has been subjected to extensive study for decades but it is only in the past few years that sufficient structural and biochemical data have emerged to give us a mechanistic understanding. Chris Higgins reviews current knowledge on the four major classes of multidrug transporter. Differences and similarities between the four are providing new insights into how multidrug resistance is achieved. This work has not yet solved pressing clinical problems, but may pave the way to strategies to beat or avoid multidrug resistance. The acquisition of multidrug resistance is a serious impediment to improved healthcare. Multidrug resistance is most frequently due to active transporters that pump a broad spectrum of chemically distinct, cytotoxic molecules out of cells, including antibiotics, antimalarials, herbicides and cancer chemotherapeutics in humans. The paradigm multidrug transporter, mammalian P-glycoprotein, was identified 30 years ago. Nonetheless, success in overcoming or circumventing multidrug resistance in a clinical setting has been modest. Recent structural and biochemical data for several multidrug transporters now provide mechanistic insights into how they work. Organisms have evolved several elegant solutions to ridding the cell of such cytotoxic compounds. Answers are emerging to questions such as how multispecificity for different drugs is achieved, why multidrug resistance arises so readily, and what chance there is of devising a clinical solution.
Audience	Academic
Author	Higgins, Christopher F
Author_xml	– givenname: Christopher F surname: Higgins fullname: Higgins, Christopher F
BackLink	http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18646841$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/17429392$$D View this record in MEDLINE/PubMed
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ContentType	Journal Article
Copyright	Springer Nature Limited 2007 2007 INIST-CNRS COPYRIGHT 2007 Nature Publishing Group Copyright Nature Publishing Group Apr 12, 2007
Copyright_xml	– notice: Springer Nature Limited 2007 – notice: 2007 INIST-CNRS – notice: COPYRIGHT 2007 Nature Publishing Group – notice: Copyright Nature Publishing Group Apr 12, 2007
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Keywords	Antineoplastic agent Antimalarial Antibiotic Three dimensional structure Molecular structure Multiple resistance Pesticides P Glycoprotein Parasiticide Mechanism of action ABC transporter Herbicide
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Snippet	The acquisition of multidrug resistance is a serious impediment to improved healthcare. Multidrug resistance is most frequently due to active transporters that... Multidrug resistance Most multidrug resistance mechanisms, for agents as diverse as antibiotics, antifungals, antimalarials, herbicides, and also for cancer...
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SubjectTerms	Animals Antibacterial agents Antibiotics Antibiotics. Antiinfectious agents. Antiparasitic agents Antiparasitic agents ATP-Binding Cassette Transporters - chemistry ATP-Binding Cassette Transporters - metabolism Biochemistry Biological and medical sciences Biomedical research Chemical compounds Drug resistance Drug Resistance, Multiple - physiology Glycoprotein Health care Herbicides Human Humanities and Social Sciences Humans Mammals Marketing Medical sciences Molecular biology multidisciplinary Multidrug Resistance-Associated Proteins - chemistry Multidrug Resistance-Associated Proteins - metabolism Organisms Pharmacology. Drug treatments Protein Conformation Proteins Pumps review-article Science Science (multidisciplinary) Structure-Activity Relationship Transcription Factors - metabolism
Title	Multiple molecular mechanisms for multidrug resistance transporters
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