The mar Locus

Thamari Schneiders; Herbert Haechler; William Yan

doi:10.1128/9781555817572.ch14

Chapter 14 : The mar Locus

Authors: Thamari Schneiders¹, Herbert Haechler², William Yan³

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Affiliations: 1: Department of Molecular Microbiology and Microbiology, Tufts University, School of Medicine, Boston, MA 02111; 2: Institute of Veterinary Bacteriology, University of Berne, Laenggassstrasse 122, 3012 Berne, Switzerland; 3: Food Directorate, Health Canada, Sir Frederick Banting Research Centre, Address Locator 2204A1, Tunney's Pasture,Ottawa, Ontario K1A 0L2, Canada

Content Type: Monograph

Publication Year: 2005

Category: Bacterial Pathogenesis

Book DOI: 10.1128/9781555817572

Chapter DOI: 10.1128/9781555817572.ch14

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Abstract:

Antibiotic resistance in bacteria can arise due to the acquisition of extrachromosomal genetic elements, and/or loss or reduction in normal gene function through mutations and enzymatic modifications. The drug resistance phenotypes conferred by these genetic determinants are usually drug and mechanism specific. The first such adaptive mechanism discovered was mapped to the multiple antibiotic resistance mar locus at 34.05 min of the Escherichia coli linkage map. As such, the discovery of the mar locus is significant for two reasons: first, it confers a multidrug resistance phenotype and second, recent findings have demonstrated that this locus controls genes in cellular metabolism, physiology, and virulence. The E. coli mar locus comprises two transcriptional units that are divergently transcribed from a common operator region, marO. Transcriptional unit 1 (TU 1) encodes MarC, which has a hydropathy profile suggestive of a putative integral transmembrane protein with six transmembrane helices. Despite MarR mediated repression, low-levels of marA are still detectable in unmutated strains, where this basal constitutive expression of marA may be needed for some expression of the marRAB locus and other members of the regulon. The gene arrangement of the marRAB locus appears to be conserved in 14 out of 53 species of Enterobacteriaceae, as was shown by Southern hybridization. Southern hybridization analysis with an E. coli marRAB probe has demonstrated that the marRAB locus is widespread and highly conserved among members of Enterobacteriaceae such as Shigella flexneri, Citrobacter freundii, Klebsiella pneumoniae, Klebsiella oxytoca, and Enterobacter cloacae.

Citation: Schneiders T, Haechler H, Yan W. 2005. The mar Locus, p 198-208. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch14

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The mar Locus

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Figure 1

Genetic organization of the mar locus. marC and marRAB are divergently transcribed from the central operator region marO ( 16 , 19 , 29 ). MarR is the repressor of the marRAB operon and does so by binding to sites within marO, depicted in the figure as Site I and Site II ( 16 , 19 ). MarA (127AA) activates the transcription of the marRAB locus by binding to the marbox (53). This activation is enhanced by the binding of the DNA bending protein Fis at the binding site also known as the “accessory” marbox ( 58 ). marB encodes for a protein (72AA) that has no known function ( 16 ). marC encodes for a putative transmembrane protein sized at 221AA with no known function ( 62 ).

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Figure 1

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Figure 2

Mutations within marR, the repressor of the marRAB locus. Mutations described in MarR in both laboratory and clinical mutants which result in a multidrug resistance phenotype ( 43 , 49 , 67 , 68 ) are shown. All the mutations have been shown to reduce or abolish the repressory effect by MarR and are localized all over the protein. The mutations shown in italics (A70T, R73C, Q90E, and R94S) are clustered in the HTH domains and result in defective proteins with little or no DNA binding activity ( 1 ). The superrepressor mutations shown in bold (D26N, G95S, V132M, and L135F) all exhibit increased DNA binding with a variable response to salicylate ( 3 ). The mutant protein Q42Amber demonstrates no repressor activity ( 1 ). The asterisk indicates a stop codon at amino acid E31 ( 68 ).

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Figure 2

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Figure 3

MarA residues important for transcriptional activation and DNA binding. Alanine mutations within the MarA protein, which result in promoter specific defects in vivo, are shown. Chemical shift mapping of the MarA-DNA complexes and β-galactosidase assays measuring the activation of the different promoter classes regulated by MarA demonstrate the effects on transcriptional activation ( 30 ). The − indicates the negative effect on transcriptional activation by MarA at the different promoters. The MarA residues shown in italics have been demonstrated to be critical for interactions with RNA polymerase at all three promoter configurations ( 21 ). Both zwf and fpr are representative of class I promoters and fumC is a class II promoter ( 51 ).

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Figure 3

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