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ARTICLE

Molecular Properties of Bacterial Multidrug Transporters

Monique Putman, Hendrik W. van Veen, Wil N. Konings
Monique Putman
Department of Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, NL-9751 NN Haren, The Netherlands
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Hendrik W. van Veen
Department of Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, NL-9751 NN Haren, The Netherlands
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Wil N. Konings
Department of Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, NL-9751 NN Haren, The Netherlands
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DOI: 10.1128/MMBR.64.4.672-693.2000
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  • Fig. 1.
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    Fig. 1.

    Resistance mechanisms in bacteria comprise (A) drug inactivation, (B) target alteration, (C) prevention of drug influx, and (D) active extrusion of drug from the cell.

  • Fig. 2.
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    Fig. 2.

    Schematic representation of the two major classes of multidrug transporters. (A) ABC-type multidrug transporters utilize the free energy of ATP hydrolysis to pump drugs out of the cell. (B) Secondary multidrug transporters mediate the extrusion of structurally unrelated drugs in a coupled exchange with protons or sodium ions.

  • Fig. 3.
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    Fig. 3.

    Structural model for the 12-TMS multidrug transporters of the MFS. The residues constituting the conserved sequence motifs are shaded.

  • Fig. 4.
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    Fig. 4.

    Structural model for the 14-TMS multidrug transporters of the MFS. The residues constituting the conserved sequence motifs are shaded.

  • Fig. 5.
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    Fig. 5.

    Structural model for multidrug transporters of the SMR family. The residues constituting the conserved sequence motifs are shaded.

  • Fig. 6.
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    Fig. 6.

    Structural model for multidrug transporters of the RND family. The residues constituting the conserved sequence motifs are shaded.

  • Fig. 7.
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    Fig. 7.

    Structural model for multidrug transporters of the ABC superfamily. Shown is the multidrug transporter LmrA, with six transmembrane helices and an NBD, containing the Walker A and B motifs and the ABC signature sequence. In view of the general four-domain organization, it may function as a homodimer. The Walker A and B motifs and the ABC signature sequence are shaded.

  • Fig. 8.
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    Fig. 8.

    Extrusion of hydrophobic drugs by multidrug transporters. Drugs are expelled from the cytoplasmic leaflet of the membrane to the external medium.

Tables

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  • Table 1.

    MFS multidrug transporters

    Multidrug transporterOrganismAccession no(s).Reference(s)
    12-TMS cluster
     Bcr Escherichia coli X63703 18
     Blt Bacillus subtilis L32599 4
     Bmr Bacillus subtilis M33768 170
     Cmr Corynebacterium glutamicum U43535 98
     EmrD Escherichia coli P31442 168
     LmrP Lactococcus lactis X89779 21
     MdfA (Cmr/CmlA) Escherichia coli Y08743, U44900 49,179
     NorA Staphylococcus aureus D90119 278
     PmrA Streptococcus pneumoniae AJ007367 63
     Tap Mycobacterium fortuitum, Mycobacterium tuberculosis AJ000283 5
    14-TMS cluster
     Bmr3 Bacillus subtilis D50098 181
     EmrB Escherichia coli P27304 135
     LfrA Mycobacterium smegmatis U40487 244
     QacA Staphylococcus aureus X56628 213
     QacB Staphylococcus aureus U22531 191
     VceB Vibrio cholerae AF012101 37
  • Table 2.

    SMR multidrug transporters

    Multidrug transporterOrganismAccession no(s).Reference(s)
    EbrA Bacillus subtilis AB029306 154
    EbrB Bacillus subtilis AB029306 154
    EmrE (MvrC) Escherichia coli Z11877, M62732 162,202
    Mmr Mycobacterium tuberculosis Z83866 42
    QacEGram-negative bacteria X68232 187
    QacEΔ1Gram-negative + gram-positive bacteria X68232 187
    QacG Staphylococcus spp. Y16944 85
    QacH Staphylococcus saprophyticus Y16945 84
    Smr (Ebr/QacC/QacD) Staphylococcus aureus X15574, M37888, M37889,M33479 71, 132, 221
    YkkC Bacillus subtilis P49856 97
    YkkD Bacillus subtilis AJ002571 97
  • Table 3.

    RND multidrug transporters

    Multidrug transporterOrganismAccession no.Reference
    AmrB Burkholderia pseudomallei AF072887 161
    AcrB Escherichia coli U00734 141
    AcrF (EnvD) Escherichia coli X57948 110
    HI0895 Haemophilus influenzae L42023 57
    MexB Pseudomonas aeruginosa L11616 198
    MexD Pseudomonas aeruginosa U57969 200
    MexF Pseudomonas aeruginosa X99514 115
    MexY Pseudomonas aeruginosa AB015853 158
    MtrD Neisseria gonorrhoeae U60099 81
    YhiV Escherichia coli U00039 143
  • Table 4.

    Consensus sequences of conserved motifs in transporters of the MFS, SMR, and RND families

    MotifConsensus sequenceaLocation
    MFS, both 12- and 14-TMS cluster
     AG x L a D r x G r k x x (x) lLoop between TMS 2 and 3
     Bl x x x R x x q G x g a aTMS 4
     Cg x x x G P x x G G x lEnd of TMS 5
    MFS, 12-TMS cluster
     D2l g x x x x x P v x PEnd of TMS 1
     GG x x x G P LEnd of TMS 11
    MFS, 14-TMS cluster
     D1l D x T v x n v A l PEnd of TMS 1
     ED x x G x x LTMS 7
     Fl g x x x G x a v x g x lTMS 13
     HW x w x F l l N v P i gTMS 6
    SMR family
     AW i x l v i A i l l E VTMS 1
     BK x s e G F t r l x P SLoop between TMS 1 and 2
     CP v G t A Y A v W t G l GStart of TMS 3
    RND family
     AG x s x v T v x F x x g t D x x x A q v q V q n k L q x A x p x L P x x V q x q g x x v x kLoop between TMS 1 and 2
     Ba l v l s a V F l P m a f f g G x t G x i y r q f s i T x v s A m a l S v x v a l t l t P A l c ATMS 6
     Cx x x G k x l x e A x x x a a x x R L R P l L M T s L a f i l G v l P l a i a t G x A G aTMS 11
     DS i N t l T l f g l v l a i G L l v D D A l V v V E N v e R v l a eTMS 4
    • ↵a The motifs were identified by alignment of amino acid sequences (190, 191). The consensus sequences of the motifs are displayed as follows: x, any amino acid; capital letters, amino acid occurs in >70% of the examined sequences; lowercase letters, amino acid occurs in >40%; (x), amino acid not always present.

  • Table 5.

    Number of sequenced and functionally characterized multidrug transporters of various families in selected bacteria

    OrganismMFSSMRRNDMATE
    12-TMS cluster14-TMS cluster
    Bacillus subtilis 21200
    Escherichia coli 31131
    Staphylococcus aureus 12300
    Mycobacterium tuberculosis 11100
    Pseudomonas aeruginosa 00040
  • Table 6.

    Reported transcriptional regulators that control the expression of multidrug transporters in bacteria

    Multidrug transporter(s)RegulatorTypeReference
    BltBltRActivator 4
    Blt, BmrMtaGlobal activator 16
    BmrBmrRActivator 3
    EmrBEmrRRepressor 136
    QacAQacRRepressor 74
    AcrBMarAGlobal activator 182
    AcrBAcrRRepressor 144
    AmrBAmrRRepressor 161
    MexBMexRRepressor 201
    MexDNfxBRepressor 200
    MexFMexTActivator 116
    MexZMexXRepressor 6
    MtrDMtrAActivator 214
    MtrDMtrRRepressor 185
  • Table 7.

    Reported drug resistance profiles of PMF- and ATP-dependent multidrug transportersa

    DrugMFSSMRRNDMATEABC
    12-TMS cluster14-TMS cluster
    BcrBltBmrCmrEmrDLmrPMdfANorAPmrATapBmr3EmrBLfrAQacAQacBVceBEbrABEmrEMmrQacEQacEΔ1QacGQacHSmrTehAYkkCDAcrBAcrFAmrBHI0895MexBMexDMexFMexYMtrDYhiVNorMYdhEHorALmrA
    Aminoglycosides−−−+b +−−−+−+−−c −+−++
    β-Lactams
     Carbapenems−−−+−−
     Cephalosporins−−−−++
     Penicillins−++−−+−d ++
    Chloramphenicol+−−−++−−−++−−−++−−+++−−+
    Glycopeptides−−−+−
    Lincosamides+−−+
    Macrolides
     14-Membered−+++−−−+−++++++++−++−−+
     15-Membered++++
     16-Membered−
    Novobiocin+−++++++
    Quinolones
     Hydrophilic++e −−−++e +−+−+−−−+−−++++−++
     Hydrophobic+e −−−−+e −−−+−++−+++−+
    Rifampin++−++−++−++
    Sulfonamides+−+
    Tetracyclines−+++−+−f +−−+−−+++−++++−−+
    Trimethoprim−−−−++−
    • ↵a +, resistance; −, no resistance.

    • ↵b MdfA expression confers resistance to kanamycin and neomycin but hypersusceptibility to spectinomycin.

    • ↵c MexCD expression confers hypersusceptibility to carbenicillin but does not affect resistance to ampicillin and penicillin.

    • ↵d MexCD expression confers hypersusceptibility to gentamicin.

    • ↵e Bmr and NorA confer a higher level of resistance to hydrophilic quinolones than to hydrophobic quinolones.

    • ↵f LfrA confers resistance to tetracycline but not to minocycline and chlortetracycline.

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Molecular Properties of Bacterial Multidrug Transporters
Monique Putman, Hendrik W. van Veen, Wil N. Konings
Microbiology and Molecular Biology Reviews Dec 2000, 64 (4) 672-693; DOI: 10.1128/MMBR.64.4.672-693.2000

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Molecular Properties of Bacterial Multidrug Transporters
Monique Putman, Hendrik W. van Veen, Wil N. Konings
Microbiology and Molecular Biology Reviews Dec 2000, 64 (4) 672-693; DOI: 10.1128/MMBR.64.4.672-693.2000
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  • Top
  • Article
    • SUMMARY
    • SECONDARY MULTIDRUG TRANSPORTERS
    • ATP-DEPENDENT MULTIDRUG TRANSPORTERS
    • REGULATION
    • RECONSTITUTION
    • SUBSTRATE BINDING
    • MECHANISM OF TRANSPORT
    • ANTIBIOTIC RESISTANCE
    • PHYSIOLOGICAL FUNCTION
    • CONCLUDING REMARKS
    • FOOTNOTES
    • REFERENCES
  • Figures & Data
  • Info & Metrics
  • PDF

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