Multidrug efflux pumps and resistance: Regulation and evolution

Current Opinion in Microbiology

Volumn 6, Issue 5, 2003, Pages 446-451

  Paulsen, Ian T ^a  

^a J CRAIG VENTER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CARRIER PROTEIN; GLYCOPROTEIN P;

CELL DIVISION; DRUG BINDING SITE; ELECTRICITY; HYDROGEN BOND; MULTIDRUG RESISTANCE; PROTEIN FUNCTION; PROTEIN STRUCTURE; REVIEW;

EID: 0242291983     PISSN: 13695274     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.mib.2003.08.005     Document Type: Review

References (53)

1. Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM: Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 1999, 39:361-398.
2. Paulsen IT, Lewis K: Microbial multidrug efflux: introduction. J Mol Microbiol Biotechnol 2001, 3:143-144.
3. Nikaido H: Prevention of drug access to bacterial targets: permeability barriers and active efflux. Science 1994, 264:382-388.
4. Murakami S, Nakashima R, Yamashita E, Yamaguchi A: Crystal structure of bacterial multidrug efflux transporter AcrB. Nature 2002, 419:587-593. This paper describes the first high-resolution structure of a secondary transporter and of a multidrug transporter and represents a very significant advance. The structure consists of three main domains, a membrane domain, a periplasmic domain with a large cavity that may bind the substrate and a head domain that probably interacts with the TolC outer membrane channel.
5. Chang G, Roth CB: Structure of MsbA from E. coli: a homolog of the multidrug resistance ATP binding cassette (ABC) transporters. Science 2001, 293:1793-1800. This paper describes the first high-resolution structure of a complete ATP-binding cassette transporter. A central chamber asymetrically lined with charged residues suggests a possible mechanism for transport.
6. Schumacher MA, Miller MC, Grkovic S, Brown MH, Skurray RA, Brennan RG: Structural mechanisms of QacR induction and multidrug recognition. Science 2001, 294:2158-2163. This paper describes the high-resolution structure of the QacR repressor complexed with six different drugs and reveals an elongated multidrug binding pocket that contains separate but linked drug binding sites.
7. Lim D, Poole K, Strynadka NC: Crystal structure of the MexR repressor of the mexRAB-oprM multidrug efflux operon of Pseudomonas aeruginosa. J Biol Chem 2002, 277:29253-29259.
8. Godsey MH, Baranova NN, Neyfakh AA, Brennan RG: Crystal structure of MtaN, a global multidrug transporter gene activator. J Biol Chem 2001, 276:47178-47184.
9. Nikaido H, Basina M, Nguyen V, Rosenberg EY: Multidrug efflux pump AcrAB of Salmonella typhimurium excretes only those beta-lactam antibiotics containing lipophilic side chains. J Bacteriol 1998, 180:4686-4692.
10. Rosenberg MF, Velarde G, Ford RC, Martin C, Berridge G, Kerr ID, Callaghan R, Schmidlin A, Wooding C, Linton KJ et al.: Repacking of the transmembrane domains of P-glycoprotein during the transport ATPase cycle. EMBO J 2001, 20:5615-5625.
11. Hirai T, Heymann JA, Shi D, Sarker R, Maloney PC, Subramaniam S: Three-dimensional structure of a bacterial oxalate transporter. Nat Struct Biol 2002, 9:597-600.
12. Paulsen IT, Brown MH, Littlejohn TG, Mitchell BA, Skurray RA: Multidrug resistance proteins QacA and QacB from Staphylococcus aureus: membrane topology and identification of residues involved in substrate specificity. Proc Natl Acad Sci USA 1996, 93:3630-3635.
13. Edgar R, Bibi E: A single membrane-embedded negative charge is critical for recognizing positively charged drugs by the Escherichia coli multidrug resistance protein MdfA. EMBO J 1999, 18:822-832.
14. Klyachko KA, Schuldiner S, Neyfakh AA: Mutations affecting substrate specificity of the Bacillus subtilis multidrug transporter Bmr. J Bacteriol 1997, 179:2189-2193.
15. Muth TR, Schuldiner S: A membrane-embedded glutamate is required for ligand binding to the multidrug transporter EmrE. EMBO J 2000, 19:234-240.
16. Elkins CA, Nikaido H: Substrate specificity of the RND-type multidrug efflux pumps AcrB and AcrD of Escherichia coli is determined predominantly by two large periplasmic loops. J Bacteriol 2002, 184:6490-6498.
17. Tikhonova EB, Wang Q, Zgurskaya HI: Chimeric analysis of the multicomponent multidrug efflux transporters from Gram-negative bacteria. J Bacteriol 2002, 184:6499-6507.
18. Mao W, Warren MS, Black DS, Satou T, Murata T, Nishino T, Gotoh N, Lomovskaya O: On the mechanism of substrate specificity by resistance nodulation division (RND)-type multidrug resistance pumps: the large periplasmic loops of MexD from Pseudomonas aeruginosa are involved in substrate recognition. Mol Microbiol 2002, 46:889-901.
19. Heldwein EE, Brennan RG: Crystal structure of the transcription activator BmrR bound to DNA and a drug. Nature 2001, 409:378-382.
20. Alekshun MN, Levy SB, Mealy TR, Seaton BA, Head JF: The crystal structure of MarR, a regulator of multiple antibiotic resistance, at 2.3 Å resolution. Nat Struct Biol 2001, 8:710-714.
21. Godsey MH, Zheleznova Heldwein EE, Brennan RG: Structural biology of bacterial multidrug resistance gene regulators. J Biol Chem 2002, 277:40169-40172.
22. Neyfakh AA: Mystery of multidrug transporters: the answer can be simple. Mol Microbiol 2002, 44:1123-1130. This provocative review discusses in detail the mechanistic basis of multidrug recognition.
23. Grkovic S, Brown MH, Skurray RA: Regulation of bacterial drug export systems. Microbiol Mol Biol Rev 2002, 66:671-701.
24. Paulsen IT, Brown MH, Skurray RA: Proton-dependent multidrug efflux systems. Microbiol Rev 1996, 60:575-608.
25. Mitchell BA, Paulsen IT, Brown MH, Skurray RA: Bioenergetics of the staphylococcal multidrug export protein QacA. Identification of distinct binding sites for monovalent and divalent cations. J Biol Chem 1999, 274:3541-3548.
26. Putman M, Koole LA, van Veen HW, Konings WN: The secondary multidrug transporter LmrP contains multiple drug interaction sites. Biochemistry 1999, 38:13900-13905.
27. Paulsen IT, Nguyen L, Sliwinski MK, Rabus R, Saier MH Jr: Microbial genome analyses: comparative transport capabilities in eighteen prokaryotes. J Mol Biol 2000, 301:75-100.
28. Tegos G, Stermitz FR, Lomovskaya O, Lewis K: Multidrug pump inhibitors uncover remarkable activity of plant antimicrobials. Antimicrob Agents Chemother 2002, 46:3133-3141. This paper demonstrates that the efficacy of plant antimicrobials can be improved by orders of magnitude by applying them in conjunction with multidrug transporter inhibitors.
29. Stermitz FR, Lorenz P, Tawara JN, Zenewicz LA, Lewis K: Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5′-methoxyhydnocarpin, a multidrug pump inhibitor. Proc Natl Acad Sci USA 2000, 97:1433-1437.
30. Seshadri R, Paulsen IT, Eisen JA, Read TD, Nelson KE, Ward NL, Tettelin H, Davidson TM, Beanan MJ, DeBoy RT et al.: Complete genome sequence of the Q-fever pathogen Coxiella burnetii. Proc Natl Acad Sci USA 2003, 100:5455-5460.
31. Pao SS, Paulsen IT, Saier MH Jr: Major facilitator superfamily. Microbiol Mol Biol Rev 1998, 62:1-34.
32. Saier MH Jr, Eng BH, Fard S, Garg J, Haggerty DA, Hutchinson WJ, Jack DL, Lai EC, Liu HJ, Nusinew DP et al.: Phylogenetic characterization of novel transport protein families revealed by genome analyses. Biochim Biophys Acta 1999, 1422:1-56.
33. Davis DR, McAlpine JB, Pazoles CJ, Talbot MK, Alder EA, White C, Jonas BM, Murray BE, Weinstock GM, Rogers BL: Enterococcus faecalis multi-drug resistance transporters: application for antibiotic discovery. J Mol Microbiol Biotechnol 2001, 3:179-184.
34. Rogers B, Decottignies A, Kolaczkowski M, Carvajal E, Balzi E, Goffeau A: The pleitropic drug ABC transporters from Saccharomyces cerevisiae. J Mol Microbiol Biotechnol 2001, 3:207-214.
35. Nishino K, Yamaguchi A: Analysis of a complete library of putative drug transporter genes in Escherichia coli. J Bacteriol 2001, 183:5803-5812. This paper applies a functional genomics approach for identifying the function of multidrug transporters through expression of all of the predicted E. coli drug efflux genes in a drug-sensitive E. coli background strain.
36. Ninio S, Rotem D, Schuldiner S: Functional analysis of novel multidrug transporters from human pathogens. J Biol Chem 2001, 276:48250-48256.
37. Giaever G, Chu AM, Ni L, Connelly C, Riles L, Veronneau S, Dow S, Lucau-Danila A, Anderson K, Andre B et al.: Functional profiling of the Saccharomyces cerevisiae genome. Nature 2002, 418:387-391.
38. Kobayashi K, Ehrlich SD, Albertini A, Amati G, Andersen KK, Arnaud M, Asai K, Ashikaga S, Aymerich S, Bessieres P et al.: Essential Bacillus subtilis genes. Proc Natl Acad Sci USA 2003, 100:4678-4683.
39. Alekshun MN, Levy SB: Regulation of chromosomally mediated multiple antibiotic resistance: the mar regulon. Antimicrob Agents Chemother 1997, 41:2067-2075.
40. Ma D, Alberti M, Lynch C, Nikaido H, Hearst JE: The local repressor AcrR plays a modulating role in the regulation of acrAB genes of Escherichia coli by global stress signals. Mol Microbiol 1996, 19:101-112.
41. Rahmati S, Yang S, Davidson AL, Zechiedrich EL: Control of the AcrAB multidrug efflux pump by quorum-sensing regulator SdiA. Mol Microbiol 2002, 43:677-685.
42. Nawrocki A, Fey SJ, Goffeau A, Roepstorff P, Larsen PM: The effects of transcription regulating genes PDR1, pdr1-3 and PDR3 in pleiotropic drug resistance. Proteomics 2001, 1:1022-1032.
43. Le Crom S, Devaux F, Marc P, Zhang X, Moye-Rowley WS, Jacq C: New insights into the pleiotropic drug resistance network from genome-wide characterization of the YRR1 transcription factor regulation system. Mol Cell Biol 2002, 22:2642-2649.
44. Baranova NN, Danchin A, Neyfakh AA: Mta, a global MerR-type regulator of the Bacillus subtilis multidrug-efflux transporters. Mol Microbiol 1999, 31:1549-1559.
45. Baranova N, Nikaido H: The baeSR two-component regulatory system activates transcription of the yegMNOB (mdtABCD) transporter gene cluster in Escherichia coli and increases its resistance to novobiocin and deoxycholate. J Bacteriol 2002, 184:4168-4176.
46. Nagakubo S, Nishino K, Hirata T, Yamaguchi A: The putative response regulator BaeR stimulates multidrug resistance of Escherichia coli via a novel multidrug exporter system, MdtABC. J Bacteriol 2002, 184:4161-4167.
47. Grkovic S, Brown MH, Roberts NJ, Paulsen IT, Skurray RA: QacR is a repressor protein that regulates expression of the Staphylococcus aureus multidrug efflux pump QacA. J Biol Chem 1998, 273:18665-18673.
48. Barbosa TM, Levy SB: Differential expression of over 60 chromosomal genes in Escherichia coli by constitutive expression of MarA. J Bacteriol 2000, 182:3467-3474.
49. Masuda N, Church GM: Escherichia coli gene expression responsive to levels of the response regulator EvgA. J Bacteriol 2002, 184:6225-6234.
50. Nishino K, Inazumi Y, Yamaguchi A: Global analysis of genes regulated by EvgA of the two-component regulatory system in Escherichia coli. J Bacteriol 2003, 185:2667-2672.
51. Yu EW, McDermott G, Zgurskaya HI, Nikaido H, Koshland DE Jr: Structural basis of multiple drug-binding capacity of the AcrB multidrug efflux pump. Science 2003, 300:976-980. This paper describes the structures of AcrB complexed with four different substrates, indicating that these ligands do bind with the large periplasmic cavity of this transporter protein.
52. Abramson J, Smirnova I, Kasho V, Verner G, Kaback HR, Iwata S: Structure and mechanism of the lactose permease of Escherichia coli. Science 2003, 301:610-615. Together with the GIpT (glycerol-3-phosphate transporter) structure paper, this represents the first high resolution of a major facilitator superfamily transporter and culminates over three decades of research on the E. coli lactose permease, and provides insight into both substrate and proton binding and translocation.
53. Huang Y, Lemieux MJ, Song J, Auer M, Wang DN: Structure and mechanism of the glycerol-3-phosphate transporter from Escherichia coli. Science 2003, 301:616-620. Together with the lactose permease structure paper, this represents the first high resolution of a major facilitator superfamily transporter. A centrally located intramembraneous pore with twin arginines at one end constitutes the substrate-binding site.