TABLE 1.

Transcriptional regulators that control expression of genes encoding bacterial drug efflux components

OrganismRegulatory protein(s)Regulator familyaFunction of regulatorLigand(s) of regulatory proteinbDrug efflux gene(s) regulatedcReference(s)
RND pump regulators
    Acinetobacter baumanniiOrf2-Orf3Two-component system??adeABC*111
    Burkholderia pseudomalleiAmrRTetRRepressor??amrAB-oprA133
    Escherichia coliAcrRTetRRepressor?acrAB*107
AcrSTetRRepressor??acrEF*156
BaeR-BaeSTwo-component system?mdtABC12, 137
EvgA-EvgSTwo-component system?yhiUV144
MarA/SoxS/RobAraCGlobal activatorsRob? (MarA/SoxSNA)acrAB* and tolC69, 70, 118, 177
MarRMarRRepressor of marADNP, Pg, Sa, MdacrAB* and tolC, via MarA6, 8, 120
    Neisseria gonorrhoeaeMtrAAraCGlobal activatorHAs?mtrCDE*184
MtrRTetRRepressor?mtrCDE* and farAB106
    Pseudomonas aeruginosaMexRMarRRepressor?mexAB-oprM*32, 170
MexTLysRActivator?mexEF-oprN*81
MexZTetRRepressor??mexXY4
NfxBLacI/GalRRepressor?mexCD-oprJ*169
    Pseudomonas putidaArpRTetRRepressor??arpABC78
    Stenotrophomonas maltophiliaSmeR-SmeSTwo-component system??smeABC100
MFS pump regulators
    Bacillus subtilisBltRMerRActivator?blt3
BmrRMerRActivatorR6G, TPP, Ao, DEC, ABM, ADCP, DDPBbmr2, 227, 244, 245
MtaMerRGlobal activator?bmr and blt13, 43
    Escherichia coliEmrRMarRRepressorCCCP, DNP, Eb, FCCP, Na, Sa, TCSemrAB* and mcbABCDEFG20, 104, 105, 238
EvgA-EvgSTwo-component system?emrKY145
TetRTetRRepressorTctetA59, 60, 153
    Staphylococcus aureusArlR-A1rSTwo-component system?norA*, via 18-kDa protein35
QacRTetRRepressorBc, Be, Ch, Cv, Dc, Eb, Mg, Pf, R6GqacA/qacB47, 48, 197, 198
  • a 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.

  • b 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.

  • c 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.