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. 1995 May;1(4):436–446.

The MarR repressor of the multiple antibiotic resistance (mar) operon in Escherichia coli: prototypic member of a family of bacterial regulatory proteins involved in sensing phenolic compounds.

M C Sulavik 1, L F Gambino 1, P F Miller 1
PMCID: PMC2230000  PMID: 8521301

Abstract

BACKGROUND: The marR gene of Escherichia coli encodes a repressor of the marRAB operon, a regulatory locus controlling multiple antibiotic resistance in this organism. Inactivation of marR results in increased expression of marA, which acts at several target genes in the cell leading to reduced antibiotic accumulation. Exposure of E. coli to sodium salicylate (SAL) induces marRAB operon transcription and antibiotic resistance. The mechanism by which SAL antagonizes MarR repressor activity is unclear. MATERIALS AND METHODS: Recombinant plasmid libraries were introduced into a reporter strain designed to identify cloned genes encoding MarR repressor activity. Computer analysis of sequence databases was also used to search for proteins related to MarR. RESULTS: A second E. coli gene, MprA, that exhibits MarR repressor activity was identified. Subsequent database searching revealed a family of 10 proteins from a variety of bacteria that share significant amino acid sequence similarity to MarR and MprA. At least four of these proteins are transcriptional repressors whose activity is antagonized by SAL or by phenolic agents structurally related to SAL. CONCLUSIONS: The MarR family is identified as a group of regulatory factors whose activity is modulated in response to environmental signals in the form of phenolic compounds. Many of these agents are plant derived. Some of the MarR homologs appear more likely to control systems expressed in animal hosts, suggesting that phenolic sensing by bacteria is important in a variety of environments and in the regulation of numerous processes.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ariza R. R., Cohen S. P., Bachhawat N., Levy S. B., Demple B. Repressor mutations in the marRAB operon that activate oxidative stress genes and multiple antibiotic resistance in Escherichia coli. J Bacteriol. 1994 Jan;176(1):143–148. doi: 10.1128/jb.176.1.143-148.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bolivar F., Rodriguez R. L., Greene P. J., Betlach M. C., Heyneker H. L., Boyer H. W., Crosa J. H., Falkow S. Construction and characterization of new cloning vehicles. II. A multipurpose cloning system. Gene. 1977;2(2):95–113. [PubMed] [Google Scholar]
  3. Burns J. L., Clark D. K. Salicylate-inducible antibiotic resistance in Pseudomonas cepacia associated with absence of a pore-forming outer membrane protein. Antimicrob Agents Chemother. 1992 Oct;36(10):2280–2285. doi: 10.1128/aac.36.10.2280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Casadaban M. J. Transposition and fusion of the lac genes to selected promoters in Escherichia coli using bacteriophage lambda and Mu. J Mol Biol. 1976 Jul 5;104(3):541–555. doi: 10.1016/0022-2836(76)90119-4. [DOI] [PubMed] [Google Scholar]
  5. Cohen S. P., Hächler H., Levy S. B. Genetic and functional analysis of the multiple antibiotic resistance (mar) locus in Escherichia coli. J Bacteriol. 1993 Mar;175(5):1484–1492. doi: 10.1128/jb.175.5.1484-1492.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cohen S. P., Levy S. B., Foulds J., Rosner J. L. Salicylate induction of antibiotic resistance in Escherichia coli: activation of the mar operon and a mar-independent pathway. J Bacteriol. 1993 Dec;175(24):7856–7862. doi: 10.1128/jb.175.24.7856-7862.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cohen S. P., McMurry L. M., Hooper D. C., Wolfson J. S., Levy S. B. Cross-resistance to fluoroquinolones in multiple-antibiotic-resistant (Mar) Escherichia coli selected by tetracycline or chloramphenicol: decreased drug accumulation associated with membrane changes in addition to OmpF reduction. Antimicrob Agents Chemother. 1989 Aug;33(8):1318–1325. doi: 10.1128/aac.33.8.1318. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cohen S. P., McMurry L. M., Levy S. B. marA locus causes decreased expression of OmpF porin in multiple-antibiotic-resistant (Mar) mutants of Escherichia coli. J Bacteriol. 1988 Dec;170(12):5416–5422. doi: 10.1128/jb.170.12.5416-5422.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cohen S. P., Yan W., Levy S. B. A multidrug resistance regulatory chromosomal locus is widespread among enteric bacteria. J Infect Dis. 1993 Aug;168(2):484–488. doi: 10.1093/infdis/168.2.484. [DOI] [PubMed] [Google Scholar]
  10. Collado-Vides J., Magasanik B., Gralla J. D. Control site location and transcriptional regulation in Escherichia coli. Microbiol Rev. 1991 Sep;55(3):371–394. doi: 10.1128/mr.55.3.371-394.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Connell N., Han Z., Moreno F., Kolter R. An E. coli promoter induced by the cessation of growth. Mol Microbiol. 1987 Sep;1(2):195–201. doi: 10.1111/j.1365-2958.1987.tb00512.x. [DOI] [PubMed] [Google Scholar]
  12. Devereux J., Haeberli P., Smithies O. A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 1984 Jan 11;12(1 Pt 1):387–395. doi: 10.1093/nar/12.1part1.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Duban M. E., Lee K., Lynn D. G. Strategies in pathogenesis: mechanistic specificity in the detection of generic signals. Mol Microbiol. 1993 Mar;7(5):637–645. doi: 10.1111/j.1365-2958.1993.tb01155.x. [DOI] [PubMed] [Google Scholar]
  14. Gambino L., Gracheck S. J., Miller P. F. Overexpression of the MarA positive regulator is sufficient to confer multiple antibiotic resistance in Escherichia coli. J Bacteriol. 1993 May;175(10):2888–2894. doi: 10.1128/jb.175.10.2888-2894.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. George A. M., Levy S. B. Amplifiable resistance to tetracycline, chloramphenicol, and other antibiotics in Escherichia coli: involvement of a non-plasmid-determined efflux of tetracycline. J Bacteriol. 1983 Aug;155(2):531–540. doi: 10.1128/jb.155.2.531-540.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. George A. M., Levy S. B. Gene in the major cotransduction gap of the Escherichia coli K-12 linkage map required for the expression of chromosomal resistance to tetracycline and other antibiotics. J Bacteriol. 1983 Aug;155(2):541–548. doi: 10.1128/jb.155.2.541-548.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Glaser P., Kunst F., Débarbouillé M., Vertès A., Danchin A., Dedonder R. A gene encoding a tyrosine tRNA synthetase is located near sacS in Bacillus subtilis. DNA Seq. 1991;1(4):251–261. doi: 10.3109/10425179109020780. [DOI] [PubMed] [Google Scholar]
  18. Greenberg J. T., Monach P., Chou J. H., Josephy P. D., Demple B. Positive control of a global antioxidant defense regulon activated by superoxide-generating agents in Escherichia coli. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6181–6185. doi: 10.1073/pnas.87.16.6181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hill T. M., Henson J. M., Kuempel P. L. The terminus region of the Escherichia coli chromosome contains two separate loci that exhibit polar inhibition of replication. Proc Natl Acad Sci U S A. 1987 Apr;84(7):1754–1758. doi: 10.1073/pnas.84.7.1754. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hooper D. C., Wolfson J. S. Bacterial resistance to the quinolone antimicrobial agents. Am J Med. 1989 Dec 29;87(6C):17S–23S. [PubMed] [Google Scholar]
  21. Jenkins J. R., Cooper R. A. Molecular cloning, expression, and analysis of the genes of the homoprotocatechuate catabolic pathway of Escherichia coli C. J Bacteriol. 1988 Nov;170(11):5317–5324. doi: 10.1128/jb.170.11.5317-5324.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kohara Y., Akiyama K., Isono K. The physical map of the whole E. coli chromosome: application of a new strategy for rapid analysis and sorting of a large genomic library. Cell. 1987 Jul 31;50(3):495–508. doi: 10.1016/0092-8674(87)90503-4. [DOI] [PubMed] [Google Scholar]
  23. Lomovskaya O., Lewis K. Emr, an Escherichia coli locus for multidrug resistance. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):8938–8942. doi: 10.1073/pnas.89.19.8938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mahenthiralingam E., Draper P., Davis E. O., Colston M. J. Cloning and sequencing of the gene which encodes the highly inducible acetamidase of Mycobacterium smegmatis. J Gen Microbiol. 1993 Mar;139(3):575–583. doi: 10.1099/00221287-139-3-575. [DOI] [PubMed] [Google Scholar]
  25. Marklund B. I., Tennent J. M., Garcia E., Hamers A., Båga M., Lindberg F., Gaastra W., Normark S. Horizontal gene transfer of the Escherichia coli pap and prs pili operons as a mechanism for the development of tissue-specific adhesive properties. Mol Microbiol. 1992 Aug;6(16):2225–2242. doi: 10.1111/j.1365-2958.1992.tb01399.x. [DOI] [PubMed] [Google Scholar]
  26. McMurry L. M., George A. M., Levy S. B. Active efflux of chloramphenicol in susceptible Escherichia coli strains and in multiple-antibiotic-resistant (Mar) mutants. Antimicrob Agents Chemother. 1994 Mar;38(3):542–546. doi: 10.1128/aac.38.3.542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Miller P. F., Gambino L. F., Sulavik M. C., Gracheck S. J. Genetic relationship between soxRS and mar loci in promoting multiple antibiotic resistance in Escherichia coli. Antimicrob Agents Chemother. 1994 Aug;38(8):1773–1779. doi: 10.1128/aac.38.8.1773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Mirel D. B., Lustre V. M., Chamberlin M. J. An operon of Bacillus subtilis motility genes transcribed by the sigma D form of RNA polymerase. J Bacteriol. 1992 Jul;174(13):4197–4204. doi: 10.1128/jb.174.13.4197-4204.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. O'Neill G., Goh S. H., Warren R. A., Kilburn D. G., Miller R. C., Jr Structure of the gene encoding the exoglucanase of Cellulomonas fimi. Gene. 1986;44(2-3):325–330. doi: 10.1016/0378-1119(86)90197-6. [DOI] [PubMed] [Google Scholar]
  30. Ochman H., Selander R. K. Standard reference strains of Escherichia coli from natural populations. J Bacteriol. 1984 Feb;157(2):690–693. doi: 10.1128/jb.157.2.690-693.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pearson W. R., Lipman D. J. Improved tools for biological sequence comparison. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2444–2448. doi: 10.1073/pnas.85.8.2444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Reverchon S., Nasser W., Robert-Baudouy J. pecS: a locus controlling pectinase, cellulase and blue pigment production in Erwinia chrysanthemi. Mol Microbiol. 1994 Mar;11(6):1127–1139. doi: 10.1111/j.1365-2958.1994.tb00389.x. [DOI] [PubMed] [Google Scholar]
  33. Roper D. I., Fawcett T., Cooper R. A. The Escherichia coli C homoprotocatechuate degradative operon: hpc gene order, direction of transcription and control of expression. Mol Gen Genet. 1993 Feb;237(1-2):241–250. doi: 10.1007/BF00282806. [DOI] [PubMed] [Google Scholar]
  34. Rosner J. L. Nonheritable resistance to chloramphenicol and other antibiotics induced by salicylates and other chemotactic repellents in Escherichia coli K-12. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8771–8774. doi: 10.1073/pnas.82.24.8771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Rosner J. L., Slonczewski J. L. Dual regulation of inaA by the multiple antibiotic resistance (mar) and superoxide (soxRS) stress response systems of Escherichia coli. J Bacteriol. 1994 Oct;176(20):6262–6269. doi: 10.1128/jb.176.20.6262-6269.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Russell C. B., Thaler D. S., Dahlquist F. W. Chromosomal transformation of Escherichia coli recD strains with linearized plasmids. J Bacteriol. 1989 May;171(5):2609–2613. doi: 10.1128/jb.171.5.2609-2613.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. SCHNEIDER H. A., ZINDER N. D. Nutrition of the host and natural resistance to infection. V. An improved assay employing genetic markers in the double strain inoculation test. J Exp Med. 1956 Feb 1;103(2):207–223. doi: 10.1084/jem.103.2.207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Sulavik M. C., Gambino L. F., Miller P. F. Analysis of the genetic requirements for inducible multiple-antibiotic resistance associated with the mar locus in Escherichia coli. J Bacteriol. 1994 Dec;176(24):7754–7756. doi: 10.1128/jb.176.24.7754-7756.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Tokito M. K., Daldal F. petR, located upstream of the fbcFBC operon encoding the cytochrome bc1 complex, is homologous to bacterial response regulators and necessary for photosynthetic and respiratory growth of Rhodobacter capsulatus. Mol Microbiol. 1992 Jun;6(12):1645–1654. doi: 10.1111/j.1365-2958.1992.tb00889.x. [DOI] [PubMed] [Google Scholar]
  40. Yalpani N., Raskin I. Salicylic acid: a systemic signal in induced plant disease resistance. Trends Microbiol. 1993 Jun;1(3):88–92. doi: 10.1016/0966-842x(93)90113-6. [DOI] [PubMed] [Google Scholar]
  41. del Castillo I., González-Pastor J. E., San Millán J. L., Moreno F. Nucleotide sequence of the Escherichia coli regulatory gene mprA and construction and characterization of mprA-deficient mutants. J Bacteriol. 1991 Jun;173(12):3924–3929. doi: 10.1128/jb.173.12.3924-3929.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. del Castillo I., Gómez J. M., Moreno F. mprA, an Escherichia coli gene that reduces growth-phase-dependent synthesis of microcins B17 and C7 and blocks osmoinduction of proU when cloned on a high-copy-number plasmid. J Bacteriol. 1990 Jan;172(1):437–445. doi: 10.1128/jb.172.1.437-445.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]

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