TABLE 1.
Transcriptional regulators that control expression of genes encoding bacterial drug efflux components
| Organism | Regulatory protein(s) | Regulator familya | Function of regulator | Ligand(s) of regulatory proteinb | Drug efflux gene(s) regulatedc | Reference(s) |
|---|---|---|---|---|---|---|
| RND pump regulators | ||||||
| Acinetobacter baumannii | Orf2-Orf3 | Two-component system? | ? | adeABC* | 111 | |
| Burkholderia pseudomallei | AmrR | TetR | Repressor? | ? | amrAB-oprA | 133 |
| Escherichia coli | AcrR | TetR | Repressor | ? | acrAB* | 107 |
| AcrS | TetR | Repressor? | ? | acrEF* | 156 | |
| BaeR-BaeS | Two-component system | ? | mdtABC | 12, 137 | ||
| EvgA-EvgS | Two-component system | ? | yhiUV | 144 | ||
| MarA/SoxS/Rob | AraC | Global activators | Rob? (MarA/SoxSNA) | acrAB* and tolC | 69, 70, 118, 177 | |
| MarR | MarR | Repressor of marA | DNP, Pg, Sa, Md | acrAB* and tolC, via MarA | 6, 8, 120 | |
| Neisseria gonorrhoeae | MtrA | AraC | Global activator | HAs? | mtrCDE* | 184 |
| MtrR | TetR | Repressor | ? | mtrCDE* and farAB | 106 | |
| Pseudomonas aeruginosa | MexR | MarR | Repressor | ? | mexAB-oprM* | 32, 170 |
| MexT | LysR | Activator | ? | mexEF-oprN* | 81 | |
| MexZ | TetR | Repressor? | ? | mexXY | 4 | |
| NfxB | LacI/GalR | Repressor | ? | mexCD-oprJ* | 169 | |
| Pseudomonas putida | ArpR | TetR | Repressor? | ? | arpABC | 78 |
| Stenotrophomonas maltophilia | SmeR-SmeS | Two-component system? | ? | smeABC | 100 | |
| MFS pump regulators | ||||||
| Bacillus subtilis | BltR | MerR | Activator | ? | blt | 3 |
| BmrR | MerR | Activator | R6G, TPP, Ao, DEC, ABM, ADCP, DDPB | bmr | 2, 227, 244, 245 | |
| Mta | MerR | Global activator | ? | bmr and blt | 13, 43 | |
| Escherichia coli | EmrR | MarR | Repressor | CCCP, DNP, Eb, FCCP, Na, Sa, TCS | emrAB* and mcbABCDEFG | 20, 104, 105, 238 |
| EvgA-EvgS | Two-component system | ? | emrKY | 145 | ||
| TetR | TetR | Repressor | Tc | tetA | 59, 60, 153 | |
| Staphylococcus aureus | ArlR-A1rS | Two-component system | ? | norA*, via 18-kDa protein | 35 | |
| QacR | TetR | Repressor | Bc, Be, Ch, Cv, Dc, Eb, Mg, Pf, R6G | qacA/qacB | 47, 48, 197, 198 |
Although two-component systems belong to a number of different families, they all consist of a transmembrane sensor of an external signal and a cytoplasmic response protein whose regulatory activities are modulated by reversible phosphorylation. Note that EvgA has been demonstrated to modulate the expression of both an RND type pump and an MFS member, yhiUV and emrKY, respectively.
Ao, astrazon orange; ABM, 5-(1-adamanthylcarboxyethyl)-3-benzyl-4-methylthiazolium; ADCP, 4-amino-3,6-dimethylbenzo[b]cycloheptano[e]pyridinium; Bc, benzalkonium; Be, berberine; CCCP, carbonyl cyanide m-chlorophenylhydrazone; Ch, chlorhexidine; Cv, crystal violet, Dc, dequalinium; DDPB, 5,6-dichloro-1,3-diethyl-2-(phenylaminovinyl)benzoimidazolium; DEC, diethyl-2,4′-cyanine; DNP, 2,4-dinitrophenol; Eb, ethidium bromide; FCCP, carbonyl cyanide p-(trifluoro-methoxy)phenylhydrazone; HAs, hydrophobic agents; Md, menadione; Mg, malachite green; Na, nalidixic acid; Pf, proflavine; Pg, plumbagin; R6G, rhodamine 6G; Sa, salicylate; Tc, tetracycline; TCS, tetrachlorosalicylanilide; TPP, tetraphenylphosphonium; ?, many of these regulatory proteins and two-component transmembrane sensors possess hypothetical ligand-binding domains for which ligands have yet to be identified. NA, not applicable, as the MarA and SoxS proteins do not possess ligand-binding domains.
Drug efflux genes or operons marked with an asterisk (*) have been observed to confer elevated antimicrobial resistance in some clinical isolates due to regulatory mutations that result in overexpression of these determinants.