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Chapter 1 : Tetracycline Resistance: Efflux, Mutation, and Other Mechanisms

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Tetracycline Resistance: Efflux, Mutation, and Other Mechanisms, Page 1 of 2

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Abstract:

Four mechanisms have evolved to counteract tetracycline. They are active efflux (keeping tetracycline out of the cytoplasm), inactivation of the tetracycline molecule, rRNA mutations (preventing tetracycline from binding to the ribosome), and ribosomal protection (preventing tetracycline from binding to the ribosome). Most of the genes that exclusively encode tetracycline efflux are positioned on transferable plasmids and/or transposons. Minicells are formed by abberant cell division in certain mutants, contain only plasmid DNA, and synthesize only (radiolabelled) plasmid-encoded proteins. Two-dimensional (2D) crystallization was done with the Tet-6H fusion protein, which was over expressed in and purified as described, with a subsequent strong anion exchange chromatography step. Tet-6H was then reconstituted into a lipid bilayer to form protein arrays in two dimensions, which were negatively stained and examined by electron microscopy. Protection by tetracycline of (mutant) Cys residues from attack by N-ethylmaleimide (NEM) is another way of identifying the substrate binding site. Mutations of His257 in TM8 of TetA(B) permit downhill tetracycline transport in vesicles but no proton antiport, suggesting a role for this residue in proton exchange. Tetracycline resistance is inducible upon addition of a subinhibitory amount of tetracycline. The (K) and (L) genes are each inducible by tetracycline and are probably regulated by translation attenuation and translation reinitiation, respectively.

Citation: Sapunaric F, Aldema-Ramos M, McMurry L. 2005. Tetracycline Resistance: Efflux, Mutation, and Other Mechanisms, p 3-18. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch1
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Figure 1a

Multiple sequence alignment of the thirteen TetA proteins of group 1 by Clustal W. The shading was done using Multiple Align Show (http://www.cbio.psu.edu/sms/multi_align.html). Residues in vertical columns in which ≥70% of the residues are identical have black backgrounds; ≥70% similar residues have gray backgrounds. Similarity groups are (Gly), (Asp, Glu), (Arg, Lys), (Ala, Phe, Ile, Leu, Met, Pro, Val, Trp), and (Cys, His, Asn, Gln, Ser, Thr, Tyr). Transmembrane helices (TM) are shown as rectangles above the alignment. Black arrowheads show critical residues in TetA of class B, and a white arrow shows the position of Fenton cleavage in classes B and D. The start codon predicted in GenBank for class Z corresponds to a Val within TM1, so we have extended the translated sequence upstream 13 amino acids to be in step with its closest relative, class 33. For convenience we have moved the better-characterized class B and class C proteins from their true positions, just above classes D and G, respectively, to the top of the alignment. Gaps assigned by Clustal W ( ) in regions before TM1 and after TM12 have been eliminated. The GenBank accession numbers are B, P02980 (Bertrand sequence [70]); C, J01749; Z, AF121000; 33, AJ420072; A, X00006; G, S52437; Y, AF070999; D, X65876; 31, AJ250203; H, U00792; J, AF038993; E, L06940; 30, AF090987.1

Citation: Sapunaric F, Aldema-Ramos M, McMurry L. 2005. Tetracycline Resistance: Efflux, Mutation, and Other Mechanisms, p 3-18. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch1
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Image of Figure 1
Figure 1

Multiple sequence alignment of the thirteen TetA proteins of group 1 by Clustal W. The shading was done using Multiple Align Show (http://www.cbio.psu.edu/sms/multi_align.html). Residues in vertical columns in which ≥70% of the residues are identical have black backgrounds; ≥70% similar residues have gray backgrounds. Similarity groups are (Gly), (Asp, Glu), (Arg, Lys), (Ala, Phe, Ile, Leu, Met, Pro, Val, Trp), and (Cys, His, Asn, Gln, Ser, Thr, Tyr). Transmembrane helices (TM) are shown as rectangles above the alignment. Black arrowheads show critical residues in TetA of class B, and a white arrow shows the position of Fenton cleavage in classes B and D. The start codon predicted in GenBank for class Z corresponds to a Val within TM1, so we have extended the translated sequence upstream 13 amino acids to be in step with its closest relative, class 33. For convenience we have moved the better-characterized class B and class C proteins from their true positions, just above classes D and G, respectively, to the top of the alignment. Gaps assigned by Clustal W ( ) in regions before TM1 and after TM12 have been eliminated. The GenBank accession numbers are B, P02980 (Bertrand sequence [70]); C, J01749; Z, AF121000; 33, AJ420072; A, X00006; G, S52437; Y, AF070999; D, X65876; 31, AJ250203; H, U00792; J, AF038993; E, L06940; 30, AF090987.1

Citation: Sapunaric F, Aldema-Ramos M, McMurry L. 2005. Tetracycline Resistance: Efflux, Mutation, and Other Mechanisms, p 3-18. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch1
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Image of Figure 2
Figure 2

The TetA(B) tetracycline/H antiporter. Transmembrane α-helices (TM) are indicated by gray rectangles numbered TM1-TM12. Circles indicate residues of class B possibly involved in substrate binding. The bracket indicates interdomain loop region corresponding to site in class A possibly involved in substrate binding. Squares indicate amino acids critical for tetracycline efflux. Triangles indicate amino acids possibly involved in local conformation change. The arrow indicates Fenton cleavage site. Scissors indicate the position where a truncation permits good activity. Horizontal lines indicate the permeability barrier for hydrophilic molecules. The circled star indicates the location in class C of its homologous Ser202. The other stars are placed at sites corresponding to those of class C and designate secondary suppressor mutations of the inactivating Ser202Phe substitution of class C.

Citation: Sapunaric F, Aldema-Ramos M, McMurry L. 2005. Tetracycline Resistance: Efflux, Mutation, and Other Mechanisms, p 3-18. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch1
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Figure 3

Projection map of 2D crystals of Tet-6H. The possible locations of the α and β halves of Tet-6H are superposed in two different trimer arrangements, each constrained to have α-α interactions. The page represents the plane of the membrane. Reprinted from Molecular Microbiology ( ) with permission of Blackwell Publishing.

Citation: Sapunaric F, Aldema-Ramos M, McMurry L. 2005. Tetracycline Resistance: Efflux, Mutation, and Other Mechanisms, p 3-18. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch1
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