Multiple molecular mechanisms for multidrug resistance transporters

• 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
• ISSN: 0028-0836; 1476-4687; 1476-4679
• DOI: 10.1038/nature05630

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.