Article Figures & Data
Figures
- 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.
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.
Structural model for the 12-TMS multidrug transporters of the MFS. The residues constituting the conserved sequence motifs are shaded.
- Fig. 4.
Structural model for the 14-TMS multidrug transporters of the MFS. The residues constituting the conserved sequence motifs are shaded.
- Fig. 5.
Structural model for multidrug transporters of the SMR family. The residues constituting the conserved sequence motifs are shaded.
- Fig. 6.
Structural model for multidrug transporters of the RND family. The residues constituting the conserved sequence motifs are shaded.
- 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.
Extrusion of hydrophobic drugs by multidrug transporters. Drugs are expelled from the cytoplasmic leaflet of the membrane to the external medium.
Tables
- Table 1.
MFS multidrug transporters
Multidrug transporter Organism Accession 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 transporter Organism Accession 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 QacE Gram-negative bacteria X68232 187 QacEΔ1 Gram-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 transporter Organism Accession 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
Motif Consensus sequencea Location MFS, both 12- and 14-TMS cluster A G x L a D r x G r k x x (x) l Loop between TMS 2 and 3 B l x x x R x x q G x g a a TMS 4 C g x x x G P x x G G x l End of TMS 5 MFS, 12-TMS cluster D2 l g x x x x x P v x P End of TMS 1 G G x x x G P L End of TMS 11 MFS, 14-TMS cluster D1 l D x T v x n v A l P End of TMS 1 E D x x G x x L TMS 7 F l g x x x G x a v x g x l TMS 13 H W x w x F l l N v P i g TMS 6 SMR family A W i x l v i A i l l E V TMS 1 B K x s e G F t r l x P S Loop between TMS 1 and 2 C P v G t A Y A v W t G l G Start of TMS 3 RND family A G 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 k Loop between TMS 1 and 2 B a 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 A TMS 6 C x 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 a TMS 11 D S 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 e TMS 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
Organism MFS SMR RND MATE 12-TMS cluster 14-TMS cluster Bacillus subtilis 2 1 2 0 0 Escherichia coli 3 1 1 3 1 Staphylococcus aureus 1 2 3 0 0 Mycobacterium tuberculosis 1 1 1 0 0 Pseudomonas aeruginosa 0 0 0 4 0 - Table 6.
Reported transcriptional regulators that control the expression of multidrug transporters in bacteria
Multidrug transporter(s) Regulator Type Reference Blt BltR Activator 4 Blt, Bmr Mta Global activator 16 Bmr BmrR Activator 3 EmrB EmrR Repressor 136 QacA QacR Repressor 74 AcrB MarA Global activator 182 AcrB AcrR Repressor 144 AmrB AmrR Repressor 161 MexB MexR Repressor 201 MexD NfxB Repressor 200 MexF MexT Activator 116 MexZ MexX Repressor 6 MtrD MtrA Activator 214 MtrD MtrR Repressor 185 - Table 7.
Reported drug resistance profiles of PMF- and ATP-dependent multidrug transportersa
Drug MFS SMR RND MATE ABC 12-TMS cluster 14-TMS cluster Bcr Blt Bmr Cmr EmrD LmrP MdfA NorA PmrA Tap Bmr3 EmrB LfrA QacA QacB VceB EbrAB EmrE Mmr QacE QacEΔ1 QacG QacH Smr TehA YkkCD AcrB AcrF AmrB HI0895 MexB MexD MexF MexY MtrD YhiV NorM YdhE HorA LmrA 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.
