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Chapter 14 : The 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

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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 locus at 34.05 min of the linkage map. As such, the discovery of the 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 locus comprises two transcriptional units that are divergently transcribed from a common operator region, . 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 are still detectable in unmutated strains, where this basal constitutive expression of may be needed for some expression of the locus and other members of the regulon. The gene arrangement of the locus appears to be conserved in 14 out of 53 species of , as was shown by Southern hybridization. Southern hybridization analysis with an probe has demonstrated that the locus is widespread and highly conserved among members of such as , , , , and .

Citation: Schneiders T, Haechler H, Yan W. 2005. The 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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Citation: Schneiders T, Haechler H, Yan W. 2005. The 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
/content/10.1128/9781555817572.chap14.fig14-1
Figure 1

Genetic organization of the locus. and are divergently transcribed from the central operator region ( ). MarR is the repressor of the operon and does so by binding to sites within , depicted in the figure as Site I and Site II ( ). MarA (127AA) activates the transcription of the 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 ( ). encodes for a protein (72AA) that has no known function ( ). encodes for a putative transmembrane protein sized at 221AA with no known function ( ).

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10.1128/9781555817572/fig14-1.gif
Image of Figure 1
Figure 1

Genetic organization of the locus. and are divergently transcribed from the central operator region ( ). MarR is the repressor of the operon and does so by binding to sites within , depicted in the figure as Site I and Site II ( ). MarA (127AA) activates the transcription of the 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 ( ). encodes for a protein (72AA) that has no known function ( ). encodes for a putative transmembrane protein sized at 221AA with no known function ( ).

Citation: Schneiders T, Haechler H, Yan W. 2005. The 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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Figure 2

Mutations within , the repressor of the locus. Mutations described in MarR in both laboratory and clinical mutants which result in a multidrug resistance phenotype ( ) 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 (and ) are clustered in the HTH domains and result in defective proteins with little or no DNA binding activity ( ). The superrepressor mutations shown in bold (and ) all exhibit increased DNA binding with a variable response to salicylate ( ). The mutant protein Q42Amber demonstrates no repressor activity ( ). The asterisk indicates a stop codon at amino acid E31 ( ).

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10.1128/9781555817572/fig14-2.gif
Image of Figure 2
Figure 2

Mutations within , the repressor of the locus. Mutations described in MarR in both laboratory and clinical mutants which result in a multidrug resistance phenotype ( ) 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 (and ) are clustered in the HTH domains and result in defective proteins with little or no DNA binding activity ( ). The superrepressor mutations shown in bold (and ) all exhibit increased DNA binding with a variable response to salicylate ( ). The mutant protein Q42Amber demonstrates no repressor activity ( ). The asterisk indicates a stop codon at amino acid E31 ( ).

Citation: Schneiders T, Haechler H, Yan W. 2005. The 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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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 ( ). 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 ( ). Both and are representative of class I promoters and is a class II promoter ( ).

10.1128/9781555817572/fig14-3_thmb.gif
10.1128/9781555817572/fig14-3.gif
Image of Figure 3
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 ( ). 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 ( ). Both and are representative of class I promoters and is a class II promoter ( ).

Citation: Schneiders T, Haechler H, Yan W. 2005. The 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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