RegulonDB RegulonDB 11.2: Operon Form
   

acrAB operon and associated TUs in Escherichia coli K-12 genome




Operon      
Name: acrAB
This page displays every known transcription unit of this operon and their known regulation.


Transcription unit       
Name: acrB
Gene(s): acrB   Genome Browser M3D Gene expression COLOMBOS
Note(s): Inactivation or inhibition of AcrAB-TolC activates the acrAB operon in response to cellular metabolism, such as enterobactin, cystein, and purine biosynthesis, and gluconeogenesis Ruiz C, Levy SB,2014 A feedback regulatory model has been proposed where the absence of a functional AcrAB-TolC pump leads to the accumulation of cellular metabolites, which usually leave cells via an AcrAB-TolC multidrug efflux pump. This accumulation results in the inactivation of AcrR and the induction of soxS and marA expression, ultimately triggering upregulation of acrAB expression to restore homeostasis Ruiz C, Levy SB,2014
Based on the bacteriostatic antibiotic-induced persister model, 37 and 9 genes were found to produce defects in rifampin- and tetracycline-induced persister formation, respectively. Only six mutants were found to overlap in both treatment-induced persister screens: recA, recC, ruvA, uvrD, fis, and acrB. Four of these mutants (recA, recC, ruvA, and uvrD) mapped to the DNA repair pathway, one mutant mapped to a global transcriptional regulator (fis), and one to a gene for an efflux protein (acrB) Cui P, Niu H, Shi W, Zhang S, Zhang W, Zhang Y,2018 Other genes that mapped to transporters, membrane biogenesis, LPS biosynthesis, flagellum biosynthesis, metabolism (folate and energy), and translation were more specific to rifampin-induced persisters Cui P, Niu H, Shi W, Zhang S, Zhang W, Zhang Y,2018
Sodium salicylate (NaSal), acetyl salicylic acid (ASA), acetaminophen (APAP), and ibuprofen contribute to antibiotic resistance by inducing the expression of both marA and acrB genes Verma T, Bhaskarla C, Sadhir I, Sreedharan S, Nandi D,2018 The induction by NaSal, ASA, and APAP is relatively higher and is partly dependent on marA, whereas ibuprofen, which induces lower antibiotic resistance, shows complete marA dependence. NaSal, ASA, APAP, and ibuprofen induce antibiotic resistance in an acrB-dependent manner Verma T, Bhaskarla C, Sadhir I, Sreedharan S, Nandi D,2018
A potential RNA G-quadruplex structure, formed by guanine-rich sequences located in the coding sequence region of the gene, was identified for acrB . This structure could regulate the expression of the gene, as observed for hemL gene expression Shao X, Zhang W, Umar MI, Wong HY, Seng Z, Xie Y, Zhang Y, Yang L, Kwok CK, Deng X,2020.
Evidence: [IC] Inferred by curator
Promoter
Name: acrBp
+1: 484685
Distance from start of the gene: 282
Sequence: tcgtgcgcgcacgtctggaagaagggcttaatccaaacgctattttagtcccgcaacaggGcgtaacccgtacgccgcgtg
Evidence: [EXP-IDA-HPT-TRANSCR-INIT-M-RACE-MAP]
Reference(s): [1] Mendoza-Vargas A., et al., 2009


Transcription unit          
Name: acrAB
Gene(s): acrB, acrA   Genome Browser M3D Gene expression COLOMBOS
Note(s): The expression of the acrAB operon, which codes for an efflux pump for drugs, is induced under oxidative stress, although this induction does not occur immediately after the stress is generated Lu C,2003 On the other hand, it has been observed that decanoate induces the acrAB operon through the Rob transcription factor, but the specific mechanism remains to be investigated Rosenberg EY,2003
Dyszel et al. showed that the transcription of the acrAB and ftsQAZ operons were only increased by the overexpression of SdiA from a plasmid, while expression of these operons was not increased by chromosomal sdiA and the presence of N-(3-oxo-hexanoyl)-L-homoserine lactone (AHL) at either 30 C or 37 C Dyszel JL,2010
In addition, this operon is affected by tetracycline antibiotic pressure. As tetracycline concentration increases, the gene expression also increases Viveiros M, Dupont M, Rodrigues L, Couto I, Davin-Regli A, Martins M, Pagès JM, Amaral L,2007 In the same experiment, acrAB expression correlated with the gene expression of marA, which encodes an activator for the operon Viveiros M, Dupont M, Rodrigues L, Couto I, Davin-Regli A, Martins M, Pagès JM, Amaral L,2007
EnvR functions as a switch for the expression of acrAB and acrEF. It is not known which compound and/or condition induces the expression of EnvR Hirakawa H,2008
The DamX and Hns proteins appear to induce indirectly the expression of the acrA gene Ruiz C,2010
The acrAB operon is upregulated when E. coli is exposed to some biocides Merchel Piovesan Pereira B, Wang X, Tagkopoulos I,2020.
Based on DNA microarray analysis, the mechanism of bacterial inactivation by carvacrol and citral was studied Chueca B, Pérez-Sáez E, Pagán R, García-Gonzalo D,2017. Treatment by both compounds caused membrane damage and activated metabolism through the production of nucleotides required for DNA and RNA synthesis and metabolic processes Chueca B, Pérez-Sáez E, Pagán R, García-Gonzalo D,2017. A total of 76 and 156 genes demonstrated significant transcriptional differences by carvacrol and citral, respectively. Genes upregulated by carvacrol treatment included the multidrug efflux pump genes acrA and mdtM, genes related to the phage shock response, pspA, pspB, pspC, pspD, pspF, and pspG, and genes whose products are important for biosynthesis of arginine (argC, argG, artJ) and purine nucleotides (purC, purM). Genes upregulated by citral treatment included purH, pyrB, and pyrI. On the other hand, mutations in several differentially expressed genes confirmed the roles of ygaV, yjbO, pspC, sdhA, yejG, and ygaV in mechanisms of inactivation by carvacrol and citral Chueca B, Pérez-Sáez E, Pagán R, García-Gonzalo D,2017.
In a study where it was shown that the L-tryptophan eradicated persister cells, it was observed that the exogenous amino acid did not affect the expression of acrAB, whereas it did affect other genes Li Y, Liu B, Guo J, Cong H, He S, Zhou H, Zhu F, Wang Q, Zhang L,2019.

Review about the regulation of the acrAB operon Weston N, Sharma P, Ricci V, Piddock LJV,2018.
Evidence: [EXP-IDA-TRANSCRIPT-LEN-DETERMINATION] Length of transcript experimentally determined
[EXP-IEP] Inferred from expression pattern
[EXP-IEP-COREGULATION] Inferred through co-regulation
Reference(s): [2] Linde HJ., et al., 2000
[3] Ma D., et al., 1993
[4] Rand JD., et al., 2002
[5] Rosenberg EY., et al., 2003
Promoter
Name: acrAp
+1: 485698
Sigma Factor: Sigma70 Sigmulon
Distance from start of the gene: 79
Sequence: gttcgtgaatttacaggcgttagatttacatacatttgtgaatgtatgtaccatagcacgAcgataatataaacgcagcaa
                              -35                     -10   +1                   
Note(s): It has been demonstrated that the acrAp promoter is not affected by σS, the stress response sigma factor Rand JD,2002.
Evidence: [COMP-AINF]
[COMP-HINF]
[COMP-HINF-POSITIONAL-IDENTIFICATION]
[EXP-IDA-TRANSCRIPTION-INIT-MAPPING]
Reference(s): [6] Eguchi Y., et al., 2003
[7] Huerta AM., et al., 2003
[8] Kobayashi A., et al., 2006
[9] Martin RG., et al., 1999
[4] Rand JD., et al., 2002
TF binding sites (TFBSs)
[AcrR,-] Phrase
Type Transcription factor Function Promoter Binding Sites Growth Conditions Evidence Confidence level (C: Confirmed, S: Strong, W: Weak) Reference(s)
LeftPos RightPos Central Rel-Pos Sequence
proximal AcrR repressor acrAp 485709 485732 -22.5 gcgttagattTACATACATTTGTGAATGTATGTAccatagcacg nd [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-DAP-SEQ], [EXP-IDA-BINDING-OF-CELLULAR-EXTRACTS], [EXP-IDA-BINDING-OF-PURIFIED-PROTEINS] C [12], [13], [14]
[EnvR,-] Phrase
Type Transcription factor Function Promoter Binding Sites Growth Conditions Evidence Confidence level (C: Confirmed, S: Strong, W: Weak) Reference(s)
LeftPos RightPos Central Rel-Pos Sequence
proximal EnvR repressor acrAp 485709 485732 -22.5 gcgttagattTACATACATTTGTGAATGTATGTAccatagcacg nd [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-AINF-SIMILAR-TO-CONSENSUS], [EXP-IDA-BINDING-OF-PURIFIED-PROTEINS] W [15]
[MarA,+] Phrase
Type Transcription factor Function Promoter Binding Sites Growth Conditions Evidence Confidence level (C: Confirmed, S: Strong, W: Weak) Reference(s)
LeftPos RightPos Central Rel-Pos Sequence
proximal MarA activator acrAp 485761 485780 -72.5 ttgcgcttctTGTTTGGTTTTTCGTGCCATatgttcgtga nd [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-AINF-SIMILAR-TO-CONSENSUS], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-IDA-BINDING-OF-PURIFIED-PROTEINS] W [9], [11]
[MprA,-] Phrase
Type Transcription factor Function Promoter Binding Sites Growth Conditions Evidence Confidence level (C: Confirmed, S: Strong, W: Weak) Reference(s)
LeftPos RightPos Central Rel-Pos Sequence
proximal MprA repressor acrAp 485704 485724 -16.0 tttacatacaTTTGTGAATGTATGTACCATAgcacgacgat nd [COMP-AINF-SIMILAR-TO-CONSENSUS] nd [11]
[PhoP,-] Phrase
Type Transcription factor Function Promoter Binding Sites Growth Conditions Evidence Confidence level (C: Confirmed, S: Strong, W: Weak) Reference(s)
LeftPos RightPos Central Rel-Pos Sequence
remote PhoP-phosphorylated repressor acrAp 485659 485675 32.0 cgcagcaatgGGTTTATTAACTTTTGAccattgacca nd [EXP-IEP-GENE-EXPRESSION-ANALYSIS] W [16]
[Rob,+] Phrase
Type Transcription factor Function Promoter Binding Sites Growth Conditions Evidence Confidence level (C: Confirmed, S: Strong, W: Weak) Reference(s)
LeftPos RightPos Central Rel-Pos Sequence
nd Rob activator acrAp nd nd nd nd nd [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [EXP-IDA-BINDING-OF-PURIFIED-PROTEINS] W [5]
[SoxS,+] Phrase
Type Transcription factor Function Promoter Binding Sites Growth Conditions Evidence Confidence level (C: Confirmed, S: Strong, W: Weak) Reference(s)
LeftPos RightPos Central Rel-Pos Sequence
proximal SoxS activator acrAp 485761 485780 -72.5 ttgcgcttctTGTTTGGTTTTTCGTGCCATatgttcgtga nd [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [EXP-IEP-RNA-SEQ], [COMP-HINF], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-CHIP-EXO-MANUAL], [EXP-IDA-BINDING-OF-PURIFIED-PROTEINS] C [9], [10]


RNA cis-regulatory element    
Regulation, transcriptional elongation  
Attenuator type: Transcriptional
Strand: reverse
  Structure type Energy LeftPos RightPos Sequence (RNA-strand)
  terminator -7.7 485776 485800 aggatgtgttGGCGCGTTTCTTGCGCTTCTTGTTtggtttttcg
  anti-terminator -9.9 485792 485828 ctgtgagaaaAGACGTAGAGCCACATCGAGGATGTGTTGGCGCGTTtcttgcgctt
Notes: "The provided "Sequence" is that of the RNA strand, i.e. U's are shown instead of T's and regulators on the reverse strand will appear as the reverse complement of the sequence delimited by LeftPos-RigtPos"


Evidence    

 [EXP-IDA-HPT-TRANSCR-INIT-M-RACE-MAP] High-throughput transcription initiation mapping

 [COMP-AINF] Inferred computationally without human oversight

 [COMP-HINF] Inferred by a human based on computational evidence

 [COMP-HINF-POSITIONAL-IDENTIFICATION] Human inference of promoter position

 [EXP-IDA-TRANSCRIPTION-INIT-MAPPING] Transcription initiation mapping

 [EXP-IEP-GENE-EXPRESSION-ANALYSIS] Gene expression analysis

 [COMP-HINF-SIMILAR-TO-CONSENSUS] A person inferred or reviewed a computer inference of sequence function based on similarity to a consensus sequence.

 [EXP-DAP-SEQ] high throughput DNA Affinity Purification (DAP) Sequencing

 [EXP-IDA-BINDING-OF-CELLULAR-EXTRACTS] Binding of cellular extracts

 [EXP-IDA-BINDING-OF-PURIFIED-PROTEINS] Binding of purified proteins

 [COMP-AINF-SIMILAR-TO-CONSENSUS] Automated inference based on similarity to consensus sequences

 [EXP-IEP-RNA-SEQ] high throughput RNA-seq evidence

 [EXP-CHIP-EXO-MANUAL] ChIP-exo evidence used in manual assertion


Reference(s)    

 [1] Mendoza-Vargas A., Olvera L., Olvera M., Grande R., Vega-Alvarado L., Taboada B., Jimenez-Jacinto V., Salgado H., Juarez K., Contreras-Moreira B., Huerta AM., Collado-Vides J., Morett E., 2009, Genome-wide identification of transcription start sites, promoters and transcription factor binding sites in E. coli., PLoS One 4(10):e7526

 [2] Linde HJ., Notka F., Metz M., Kochanowski B., Heisig P., Lehn N., 2000, In vivo increase in resistance to ciprofloxacin in Escherichia coli associated with deletion of the C-terminal part of MarR., Antimicrob Agents Chemother 44(7):1865-8

 [3] Ma D., Cook DN., Alberti M., Pon NG., Nikaido H., Hearst JE., 1993, Molecular cloning and characterization of acrA and acrE genes of Escherichia coli., J Bacteriol 175(19):6299-313

 [4] Rand JD., Danby SG., Greenway DL., England RR., 2002, Increased expression of the multidrug efflux genes acrAB occurs during slow growth of Escherichia coli., FEMS Microbiol Lett 207(1):91-5

 [5] Rosenberg EY., Bertenthal D., Nilles ML., Bertrand KP., Nikaido H., 2003, Bile salts and fatty acids induce the expression of Escherichia coli AcrAB multidrug efflux pump through their interaction with Rob regulatory protein., Mol Microbiol 48(6):1609-19

 [6] Eguchi Y., Oshima T., Mori H., Aono R., Yamamoto K., Ishihama A., Utsumi R., 2003, Transcriptional regulation of drug efflux genes by EvgAS, a two-component system in Escherichia coli., Microbiology 149(Pt 10):2819-28

 [7] Huerta AM., Collado-Vides J., 2003, Sigma70 promoters in Escherichia coli: specific transcription in dense regions of overlapping promoter-like signals., J Mol Biol 333(2):261-78

 [8] Kobayashi A., Hirakawa H., Hirata T., Nishino K., Yamaguchi A., 2006, Growth phase-dependent expression of drug exporters in Escherichia coli and its contribution to drug tolerance., J Bacteriol 188(16):5693-703

 [9] Martin RG., Gillette WK., Rhee S., Rosner JL., 1999, Structural requirements for marbox function in transcriptional activation of mar/sox/rob regulon promoters in Escherichia coli: sequence, orientation and spatial relationship to the core promoter., Mol Microbiol 34(3):431-41

 [10] Seo SW., Kim D., Szubin R., Palsson BO., 2015, Genome-wide Reconstruction of OxyR and SoxRS Transcriptional Regulatory Networks under Oxidative Stress in Escherichia coli K-12 MG1655., Cell Rep 12(8):1289-99

 [11] Rodionov DA., Gelfand MS., Mironov AA., Rakhmaninova AB., 2001, Comparative approach to analysis of regulation in complete genomes: multidrug resistance systems in gamma-proteobacteria., J Mol Microbiol Biotechnol 3(2):319-24

 [12] Lee JO., Cho KS., Kim OB., 2014, Overproduction of AcrR increases organic solvent tolerance mediated by modulation of SoxS regulon in Escherichia coli., Appl Microbiol Biotechnol 98(20):8763-73

 [13] Ma D., Alberti M., Lynch C., Nikaido H., Hearst JE., 1996, The local repressor AcrR plays a modulating role in the regulation of acrAB genes of Escherichia coli by global stress signals., Mol Microbiol 19(1):101-12

 [14] Su CC., Rutherford DJ., Yu EW., 2007, Characterization of the multidrug efflux regulator AcrR from Escherichia coli., Biochem Biophys Res Commun 361(1):85-90

 [15] Hirakawa H., Takumi-Kobayashi A., Theisen U., Hirata T., Nishino K., Yamaguchi A., 2008, AcrS/EnvR represses expression of the acrAB multidrug efflux genes in Escherichia coli., J Bacteriol 190(18):6276-9

 [16] Monsieurs P., De Keersmaecker S., Navarre WW., Bader MW., De Smet F., McClelland M., Fang FC., De Moor B., Vanderleyden J., Marchal K., 2005, Comparison of the PhoPQ regulon in Escherichia coli and Salmonella typhimurium., J Mol Evol 60(4):462-74

RegulonDB