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Chapter 64 : Tetracycline Resistance Determinants in Gram-Positive Bacteria

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Abstract:

The emergence of tetracycline resistance in the mid-1950s, initially in gram-negative bacteria and then in gram-positive bacteria, resulted in the declining usefulness of tetracyclines. There are three different tetracycline resistance mechanisms of clinical importance found among gram-positive organisms. They are active efflux, ribosomal protection, and mutated rRNA. Multidrug transporters are able to efflux substrates that are chemically diverse, and some from gram-negative bacteria include tetracycline in their repertoire, for example, AcrAB () and MexAB/OprM ( sp.). The only multidrug transporter from gram-positive bacteria known to transport tetracycline is the TetAB transporter from . The emphasis in this chapter is on proteins found in gram-positive organisms. The Asp-66–Ala mutation may directly or indirectly prevent tetracycline binding, or it may prevent a conformational change in motif A caused by binding elsewhere. In the case of the gram-positive Tet(L) and Tet(K) proteins, substitutions at Asp-74, corresponding to the essential Asp-66 in TetA(B), only partly decrease tetracycline resistance, although efflux activity is more severely affected. Tetracycline resistance determinants are widely spread among different gram-positive genera. Tetracycline resistance spreads because the determinants are often located on conjugative elements, either plasmids or transposons.

Citation: McMurry L, Levy S. 2006. Tetracycline Resistance Determinants in Gram-Positive Bacteria, p 801-820. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch64
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FIGURE 1

Structure of tetracycline and some of its clinically used analogs.

Citation: McMurry L, Levy S. 2006. Tetracycline Resistance Determinants in Gram-Positive Bacteria, p 801-820. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch64
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Image of FIGURE 2
FIGURE 2

Predicted or verified (see text) transmembrane topology of tetracycline efflux proteins from groups 1 to 4. The inset at the bottom shows the consensus motif A sequence in loop 2 to 3, followed by the motif A sequences for Tet proteins of groups 1 to 4. L chr, the protein from the chromosomal Tet L determinant. The topologies of groups 5 and 6 are less certain (see text) and are not included. In group 1, the better-studied gram-negative TetA(B) protein replaces the gram-positive TetA(Z) and TetA( ) proteins. Residues marked in TetA(B) are identical in TetA(Z) and TetA( ), except for H257 and residue 253. Transmembrane α-helices (presumed) are shown in gray and are numbered. Charged residues predicted or known to be within transmembrane helices are shown with a large font and lettering. In motif A of TetA(B), a plus or minus sign indicates the necessity of that charge at that site. Gly-62 and, to a lesser extent, Gly-69 probably cause a β-turn (see references and ). Other residues mentioned in the text are shown in small fonts without letters. An asterisk indicates residues possibly involved in tetracycline binding in TetA(B). A large arrow indicates the Fe-mediated cleavage site within helix 7, and the dotted line there shows the membrane impermeability barrier, which is not marked in other helices. Small arrows show regions in Tcr3 that are longer than similar regions in Tet(K) and Tet(L). A dotted line in group 3 similarly shows where OtrB has regions longer than those in Tcr3.

Citation: McMurry L, Levy S. 2006. Tetracycline Resistance Determinants in Gram-Positive Bacteria, p 801-820. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch64
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Tables

Generic image for table
TABLE 1

Tetracycline resistance genes from gram-positive organisms: efflux

A specific sequenced gene was chosen to represent each class. Information in the first eight columns applies to this gene. The last column indicates the locations of typical class members. Groups coincide well with the data of Guillaume et al. ( ), except that (the gram-negative) Tet Y has been moved from group 6 into group 1.

Number of amino acid residues in protein. For class Z, the N-terminal residue has been located 13 residues upstream of that originally annotated, to coincide with the putative translational start of Tet( ) and to agree with the topology of other group 1 proteins.

C, chromosome; P, plasmid; P**, conjugative plasmid; T, conjugative transposon.

The two (K) sequences, one from 1986 and one from 1993, are identical; in intervening years, inaccurate sequences were reported ( ).

Some plasmid-mediated Tet L determinants are constitutive (see text).

Citation: McMurry L, Levy S. 2006. Tetracycline Resistance Determinants in Gram-Positive Bacteria, p 801-820. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch64
Generic image for table
TABLE 2

Tetracycline resistance genes from gram-positive organisms: ribosomal protection

A specific sequenced gene was chosen to represent each class. Information in the first eight columns applies to this gene. The last column indicates the locations of typical class members.

AA, number of amino acid residues in the protein.

C, chromosome; P, plasmid; P**, conjugative plasmid; T, conjugative transposon.

A (O) sequence taken from the gram-negative is included because of the availability of additional upstream sequences of interest.

First discovered in a gram-negative bacterium, but also found in gram-positive organisms (see Table 3 ).

has recently been reclassified as a gram-positive-like organism ( ).

Citation: McMurry L, Levy S. 2006. Tetracycline Resistance Determinants in Gram-Positive Bacteria, p 801-820. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch64
Generic image for table
TABLE 3

Distribution of tetracycline resistance determinants in gram-positive and certain other bacteria

Includes , , , , , and spp. Based on reference , with additions from references (for ), , and . sp. has been reclassified as a gram-positive-like organism ( ); we have therefore included the related genera and .

In addition to the references listed in footnote , reference was also used.

Citation: McMurry L, Levy S. 2006. Tetracycline Resistance Determinants in Gram-Positive Bacteria, p 801-820. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch64

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