Microbiology and Molecular Biology Reviews, September 1999, p. 507-522, Vol. 63, No. 3
Department of Microbiology, The University of
Georgia, Athens, Georgia 30602-2605,1 and
CSIRO Molecular Science, North Ryde, New South Wales 1690, Australia2
1092-2172/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Transposon Tn21, Flagship of the
Floating Genome
SUMMARY
INTRODUCTION
TRANSPOSITION COMPONENTS
Tn3-Like Transposable Elements
Subtype
Tn21
Tn21, a Class II Replicative Transposon
tnp transposition module.
Putative tnpM.
MER OPERON
Mercury Resistance
mer Genes
Metalloregulator (merR).
Mercury transport genes (merT,
merP, and merC).
Mercuric reductase gene (merA).
Secondary regulatory gene (merD).
Putative merE (urf1).
urf2 and the Hypothetical urf2M
IN2 INTEGRON
5'-Conserved Segment
aadA1 Cassette
3'-Conserved Segment
tni Transposition Module
IS1326 Insertion Sequence
IS1353 Insertion Sequence
TN21 EVOLUTION
Model for Tn21 Evolution
Model for In2 Evolution
Codon Usage Comparisons
TN21 SAILS THE WORLD
Environmental Occurrences
Clinical Occurrences
CONCLUDING REMARKS
ACKNOWLEDGMENTS
REFERENCES
SUMMARY
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The transposon Tn21 and a group of closely related transposons (the Tn21 family) are involved in the global dissemination of antibiotic resistance determinants in gram-negative facultative bacteria. The molecular basis for their involvement is carriage by the Tn21 family of a mobile DNA element (the integron) encoding a site-specific system for the acquisition of multiple antibiotic resistance genes. The paradigm example, Tn21, also carries genes for its own transposition and a mercury resistance (mer) operon. We have compiled the entire 19,671-bp sequence of Tn21 and assessed the possible origins and functions of the genes it contains. Our assessment adds molecular detail to previous models of the evolution of Tn21 and is consistent with the insertion of the integron In2 into an ancestral Tn501-like mer transposon. Codon usage analysis indicates distinct host origins for the ancestral mer operon, the integron, and the gene cassette and two insertion sequences which lie within the integron. The sole gene of unknown function in the integron, orf5, resembles a puromycin-modifying enzyme from an antibiotic producing bacterium. A possible seventh gene in the mer operon (merE), perhaps with a role in Hg(II) transport, lies in the junction between the integron and the mer operon. Analysis of the region interrupted by insertion of the integron suggests that the putative transposition regulator, tnpM, is the C-terminal vestige of a tyrosine kinase sensor present in the ancestral mer transposon. The extensive dissemination of the Tn21 family may have resulted from the fortuitous association of a genetic element for accumulating multiple antibiotic resistances (the integron) with one conferring resistance to a toxic metal at a time when clinical, agricultural, and industrial practices were rapidly increasing the exposure to both types of selective agents. The compendium offered here will provide a reference point for ongoing observations of related elements in multiply resistant strains emerging worldwide.
INTRODUCTION
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With the rich insights provided by the burgeoning information on entire prokaryotic genome sequences, it is important to recall that a significant percentage of the DNA in natural isolates of many eubacteria is in the form of extrachromosomal elements called plasmids. Many of these elements are transferable even very widely across species and genus boundaries. In addition to genes for their own maintenance and transfer, these ubiquitous genetic elements frequently carry embedded mobile genetic elements called transposons, which are capable of moving from one carrier replicon to another.
Much of what we understand about DNA replication and recombination in general has been learned through the study of such plasmids and transposons in the eubacteria. Although they are major agents of the horizontal gene exchange which complicates simple phylogenetic analyses of whole bacterial genome sequences, there are no compendia of the complete sequences of the genomes of these peripatetic members of the "floating genome." We have compiled and annotated sequence information for one of the first recognized, largest, and most widely distributed examples of this group, the multiply composite transposon Tn21.
This analysis has been stimulated by the demonstrated involvement of the Tn21-family in the global dissemination of antibiotic resistance determinants (16-18) and consequent interest in the processes involved in the accumulation and exchange of resistance loci by plasmids and transposons. Horizontal and vertical transfer of antibiotic resistance genes in members of the family Enterobacteriaceae and Pseudomonas is mostly due to large broad-host-range plasmids and to the transposons they carry and share with other replicons (17). Many transposons encoding multiple antibiotic resistances in gram-negative members of the Enterobacteriaceae belong to the Tn21 subgroup of the Tn3 family of transposable elements (29, 63). Transposon Tn21 and many of its closest relatives carry within them a potentially independently mobile DNA element called an integron. The integron encodes a RecA-independent, site-specific integration system that is responsible for the acquisition of multiple small mobile elements called gene cassettes that encode antibiotic resistance genes (35, 60, 74, 104, 109). Tn21 also carries the genes involved in its own transposition (tnp) and a mercury resistance (mer) operon (29, 98).
Transposon Tn21 itself is carried by plasmid NR1 (R100), which was originally isolated from Shigella flexneri in Japan in the late 1950s (70). NR1 is a 94.5-kb, self-transmissible, multiple-antibiotic resistance plasmid (Fig. 1) and is the archetype of a large collection of similar R-plasmids that have been discovered worldwide (18, 116). NR1, which belongs to the FII incompatibility group of R-plasmids, was initially considered to have two components: a resistance transfer factor (RTF), which carries the genes for self-transmissibility (tra) and autonomous replication (rep), and a resistance determinant (R-det), which contains a composite Tn9-like transposon, carrying the catA1 (catI) gene, and transposon Tn21 (120). The R-det component is bound by direct repeats (IS1a and IS1b) and is itself transposable as Tn2670 (37, 43). Tn21 is an independent transposon within the R-det and is bounded by inverted repeats IRl and IRr (19, 28, 127). Located in the RTF region of NR1 is transposon Tn10, which carries tetR (tet repressor) and tetA (confers tetracycline resistance) and is bounded by IS10R and IS10L (46). The other major functional loci within the RTF are the origin of conjugative transfer (oriT) gene and the transfer (tra) genes.
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Recently, the last section of the Tn21 transposon was
sequenced (5), revealing that Tn21 itself
includes four discrete mobile elements: a class 1 integron, the
aadA1 gene cassette contained in the integron, and two
insertion sequences, IS1326 and IS1353 (Table
1 and Fig.
2). We have assembled five overlapping
GenBank sequences (accession no. X04891, M10791, X12870, U42226, and
J01730 [Table 2]) and updated the
annotation of the assembled sequence of 19,671 bp (GenBank accession
no. AF071413 [Tables 3 to
5]).
Due to the growing interest in integrons, we present the
Tn21 sequence with the transposition genes on the left and the mer genes on the right, since this allows the components
to be viewed in the orientation familiar to those studying the integron itself.
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TRANSPOSITION COMPONENTS
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Tn3-Like Transposable Elements
Subtype
Tn21
Tn3-like transposable elements are characterized by flanking inverted repeats of about 38 bp and have two genes, tnpA and tnpR, which encode a transposase and resolvase, respectively (29, 95). The tnpR gene and the res site (the site at which the resolvase acts) are located just upstream of tnpA. In the Tn21 transposon subgroup, the tnpA and tnpR genes are transcribed in the same direction. The TnpA proteins of this transposon family are at least 70% homologous to each other, as are their TnpR proteins (29). Transposases from this family share, as do many other transposases, a DD(35)E motif, which may form part of the catalytic center (125).
Tn21, a Class II Replicative Transposon
Transposition of transposon Tn21 is carried out by the transposase, TnpA (29). The sites of insertion, defined by a 5-bp duplication of target DNA, are usually AT rich but have no other obvious consensus sequence (77). Replicative transposition of Tn21 involves specific recognition of and binding to the terminal inverted-repeat (IR) elements of Tn21 by TnpA, which then mediates joining of the donor and recipient replicons (77). This cointegrate intermediate contains a copy of Tn21 and is resolved by the action of the tnpR gene product, a resolvase which acts at a specific site (res) adjacent to the tnpR gene (85).
The resolvase catalyzes site-specific recombination between supercoiled DNA and two directly repeated copies of the transposon DNA (102). Resolvase subunits bind to the three subsites (I, II, and III) of res within both recombination loci (100). These protein-DNA assemblies at each res site then interact with each other to form a synaptic complex (101) in which the resolvase separates the cointegrate to give a new recombinant replicon with one copy of the transposon and the original donor replicon, which retains its copy. In the Tn21 subgroup of transposons, the transposase-IR interactions and the resolvases are interchangeable; e.g., Tn21 tnpA can act on the Tn501 IRs and Tn21 tnpR can act on the Tn501 res site (29).
tnp transposition module. The positions of the important features of the tnp region of Tn21 are presented in Table 3, and those of the IRmer region are presented in Table 4. The tnp region begins with the left IR (designated IRtnp) and extends to include the res site. The right end of Tn21 (designated IRmer) lies beyond the end of the merR gene. These left and right Tn21 IRs are 38-bp imperfect repeats (three base differences). tnpA is the largest structural gene in the transposon, encoding a 988-amino-acid (aa) transposase which terminates 5 bp into IRtnp (115). An independent promoter for tnpA has been suggested (29, 42) to occur within the last 80 bp of the tnpR gene. tnpR is 561 bp and terminates 2 bp before the putative initiation codon of tnpA. The predicted promoter region for the tnpR gene (and possibly the tnpA gene) is located within the res site (22, 31). The 129-bp res site has three resolvase binding sites (I, II, and III) with the recombination crossover point located in resI (85).
Putative tnpM.
An adjacent putative gene of
undefined function, tnpM (351 bp), was originally defined as
starting at the junction of the tnp region and the integron
IRi (leftward inverted repeat) and terminating within
resI (42). The ribosomal binding site and the
promoter 
10 and 35 regions for this putative tnpM gene
are located within the integron, in IRi and in the
noncoding region downstream of the intI1 gene, respectively.
35 promoter region of
tnpM. These authors concluded that tnpM was not
necessary for transposition. However, Hyde and Tu (42)
proposed that the tnpM gene produces a protein which
enhances Tn21 transposition and suppresses cointegrate
resolution. The basis for their proposal was the finding that a strain
carrying a nonsense mutation in the tnpM reading frame was
less effective than its parent in effecting Tn21
transposition and resolution. Furthermore, they observed that when a
multicopy derivative carrying only Tn21 tnpM was
present, transposition of Tn21 increased by 2.5-fold and
resolution decreased 22-fold. They also noted an open reading frame
(ORF) in Tn501 (orf2) at the same relative location and
orientation, whose product was 84.6% similar to the putative
Tn21 TnpM protein (Fig. 3). These similarities led Hyde and Tu to examine whether transposition and
resolution of Tn501 was susceptible to modulation by
Tn21 tnpM. They found that with the Tn21
tnpM gene in trans, transposition of Tn501
also increased by 2.5-fold and resolution decreased by 1.5-fold.
However, no TnpM protein has been demonstrated. Thus, at present,
neither the exact nature of the control for TnpA and TnpR nor the role
of the putative TnpM is understood. We offer here the possible
alternative that the tnpM reading frame is actually derived
from a longer ORF which was interrupted by the insertion of In2 (see
below). These alternatives are not necessarily mutually exclusive.
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MER OPERON
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Mercury Resistance
Divalent mercuric ion, Hg(II), has a high affinity for thiol groups of proteins and for this reason is extremely toxic in biological systems. The current model of the mercury resistance (Hgr) mechanism of gram-negative bacteria posits that Hg(II) enters the periplasm and is bound to a pair of cysteine residues in MerP which transfer Hg(II) to cysteine residues in MerT or MerC. The latter move the ion across the cytoplasmic membrane in a series of ligand exchange reactions, resulting in the delivery of Hg(II) to the active site of the cytoplasmic flavin disulfide oxidoreductase, mercuric reductase (MerA) (98). Mercuric reductase catalyzes the reduction of Hg(II) to the highly volatile and less reactive monoatomic gas, Hg0, which diffuses from the cell and from the medium.
mer Genes
The mer region (Table 4) (1, 65, 66), flanked on its right by Tn21 IRmer and on its left by the rightward IR (designated IRt) of the integron, is sufficient to confer resistance to Hg(II). The mercury resistance operon of Tn21 contains two regulatory genes, merR and merD, and four structural genes, merT, merP, merC, and merA, encoding the NADH-dependent flavin oxidoreductase, mercuric reductase (MerA); two inner membrane proteins (MerT and MerC); and a periplasmic protein (MerP). Further genes may also play a role in mercury resistance.
Metalloregulator (merR).
The
merR gene is at the opposite end of the transposon to the
tnpA gene, and, like tnpA, merR
terminates 5 bp into the IR bounding Tn21. The
merR gene and the merTPCAD genes are transcribed divergently from a compact 71-bp promoter/operator (merOP)
region in which their respective 10 RNA polymerase recognition
hexamers overlap by 4 bp (39, 73). MerR binds a dyadic
operator (merO) in the 19-bp spacer between the
merTPCAD 35 and 10 promoter hexamers, and in the absence
of Hg(II) it represses their expression. Since the dyadic binding site
is also superimposed on the merR transcriptional start
position, MerR represses its own synthesis (96). The metal
binding domain of MerR, containing residues from Cys80 to Cys128, is
sufficient to form a single, dimeric, trigonally coordinate,
high-affinity Hg(II) binding site (126). When MerR binds
Hg(II), an allosteric change in MerR allows transcription of the
mer structural genes without changing the level of slightly leaky repression of MerR (86, 107). MerR also
sequesters RNA polymerase at the merT promoter, forming a
stable preinitiation complex (39). MerR contacts the 
,
, and 
70 subunits of RNA polymerase both in the
preinitiation and Hg(II)-activated promoter complexes (51).
Mercury transport genes (merT,
merP, and merC).
The products of the first
three structural genes of the mer operon are involved in
uptake of Hg(II) into the cell. These small genes are tightly spaced,
with the merT gene (351 bp) separated by only 13 bp from the
merP gene (276 bp) and merP separated from the
merC gene (423 bp) by 35 bp. Both MerT and MerC are inner membrane proteins (106) and are predicted to have three and
four transmembrane-spanning -helices, respectively. MerP is located in the periplasm (106) and is composed of four -strands
and two -helices (103). Both cysteine residues (Cys33 and
Cys36) in MerP are required for Hg(II) binding in vitro
(90), and this is one of only two proteins of the operon
whose structure is presently known (103). MerP is believed
to transfer Hg(II) to the amino-terminal cysteine pair (Cys24 and
Cys25) of MerT (36, 67). How Hg(II) is then transferred
inside the cell to MerA is unknown. The MerP sequence constitutes the
index example of the HMA motif found in several prokaryotic metal
transporters (62, 72, 97) and in the human Cu transporters,
MNK and WND (8).
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Mercuric reductase gene (merA).
merA, which begins 51 bp on the 3' side of merC,
encodes a cytoplasmic, redox enzyme (564 aa) and is the largest gene in
the mer operon. MerA belongs to the class I pyridine
nucleotide-disulfide oxidoreductases and has sequence and structural
homology to glutathione reductase and other disulfide oxidoreductases
(93). The amino terminus of merA and of the
merP gene (signal sequence excluded) are extensively
homologous, indicating a fusion between ancestral genes for MerP and
for glutathione reductase. MerA functions as an 2
homodimer, and two pairs of cysteine residues, a redox-active pair
(Cys135 and Cys140) from one subunit of MerA and a carboxyl-terminal pair (Cys561 and Cys562) from the other subunit of MerA, form the
catalytic site (21). MerA uses two hydrides from two NADPH molecules for the reduction of flavin adenine dinucleotide, which in
turn reduces Hg(II) bound to the redox-active cysteines of the enzyme
(89, 93). Studies by Miller et al. (64) have shown that pyridine nucleotide complexed dimers of the enzyme are
asymmetric. Since the reduced enzyme EH2-NADPH complex is the reductant
of Hg(II), these observations suggest that the enzyme may function
asymmetrically during catalysis. Miller et al. (64) have
proposed an alternating-sites model for the catalytic reduction of
Hg(II), where both subunits of the dimer function in catalysis but the
steps are staggered, allowing subunits to reverse roles after part of
the reduction so that the enzyme can both bind Hg(II) very tightly and
reduce it (64).
Secondary regulatory gene (merD). The most promoter-distal experimentally defined gene of the mer operon, merD (363 bp), begins 17 bp downstream of merA (54). The MerD protein is made in very small amounts (54). The suggested role of MerD is that of a down-regulator of the mer operon which binds weakly to the merOP region; MerD null mutants show increased operon expression (69).
Putative merE (urf1). Two other reading frames at the end of the mer operon in Tn21 are also frequently found in other mer operons (Fig. 3), but experimental definition for them is lacking. The first of these, which overlaps the 3' end of merD by 4 bp, is a 237-bp ORF variously designated orf1 (6, 27), urf1 (7, 84, 124), urf (45), or merE (47, 49) (Table 6). Putative merE has a GTG start codon and an appropriately placed Shine-Dalgarno consensus sequence (AGGAGG) and encodes a predicted polypeptide of 78 aa. There is no evidence to indicate whether this ORF is transcribed or translated, and no null or nonsense mutations in it have been examined for their effect on Hg resistance. However, 10 highly similar (80.4% ± 8.6% as determined by GAP; Genetics Computer Group, Inc. [GCG], Madison, Wis.) putative MerE protein sequences (listed in Table 6) from other mer loci of gram-negative bacteria have been reported. Of the 10 putative merE genes, 9 lie in the same position and orientation as the urf1 in the Tn21 mer locus (Fig. 3) and the other is located 5' to the merC gene of a Thiobacillus mer locus (Table 6) (45). The putative Tn21 merE is also 58.0% similar to merT (previously called ORF2) in the mer locus of a gram-positive bacterium, Bacillus sp. strain RC607 (114). These 12 sequences are the only homologs of Tn21 merE in the database.
Cysteine pairs are characteristically found in Mer proteins, and putative MerE has a cysteine pair (Cys28 and Cys30) which, with adjacent residues (LTCPCHL), is conserved in all of these putative MerE polypeptides. The predicted secondary structure of MerE would have two transmembrane helices with the cysteine pair positioned approximately in the middle of the first helix (87, 99). That the first cysteine pair is also found in the same predicted position in MerT, MerC, and MerF suggests that MerE may play a role in Hg(II) transport.urf2 and the Hypothetical urf2M
Overlapping the 3' end of merE by 4 bp is the second reading frame of unknown function, urf2 (708 bp), whose stop codon lies 67 bp inside the right end of the integron rightward boundary at IRt. However, if the integron and one of its flanking 5-bp direct repeats were removed, urf2 would fuse in frame with the putative tnpM gene to produce a 987-bp hypothetical gene which we designate Tn21 urf2M (Fig. 3). Its 328-aa predicted product, Urf2M, is 76.9% identical and 79.3% similar to the predicted 329-aa product of orf2 found in transposon Tn501. Transposon Tn501 is a Tn21 subgroup transposon with a gene organization similar to that of Tn21 but lacking both merC and the integron (29). Also, the predicted product of urf2 in the mer operon of plasmid pPB is 78.7% similar to Tn21 Urf2M. The predicted product of orf2 (an incomplete sequence) in the mer operon of plasmid pDU1358 is 80.0% similar to Tn21 Urf2M.
Further, part of Tn21 Urf2M (226 of 328 aa) (Fig. 3) is also about 62% similar to a group of hypothetical proteins which belong to the YEGE/YHDA/YHJK/YJCC family of proteins (4, 121). These putative proteins (referred to here as Y proteins) are characterized by transmembrane regions and tyrosine kinase domains as found in two-component signal regulators (41). The carboxyl termini of the Y proteins are 62.3% ± 1.0% similar (40.3% ± 3.5% identical) to Tn21 Urf2M beginning at aa 22 and ending 35 aa into the beginning of putative TnpM (a total of 226 contiguous residues). This similarity to the carboxyl termini of the Y proteins also occurs in Tn501 Orf2 and pPB Urf2.
These similarities suggest that before In2 insertion, a distinct insertion or deletion occurred, forming an ORF (encoding a 328-aa product) between the mer and tnp genes or within a gene at the 3' end of an ancestral mer operon. Possible remnants of this event are the last 66 aa of Tn21 TnpM, the last 67 aa of Tn501 Orf2 and pPB Urf2, and the last 70 aa of Tn5041 Urf2, pKLH2 Urf2y, and Tn5036 Urf2y, which are conserved (including three conserved cysteine pairs) (Fig. 3). Ribosomal binding sites in front of possible translation start sites occur in the genes encoding each of the aforementioned 66-, 67-, and 70-aa predicted products, suggesting that a smaller gene may be present in the larger ORFs.
To assess the possible origin of Tn21 urf2M and
Tn501 orf2, we compared codon usage patterns of
Tn21 urf2M with those of the Tn21 and Tn501
merA and tnpA genes (Tables
7 and 8).
The GCG program Correspond (24) compares two codon frequency
tables (20) and yields the residuals statistic
D2 (Table 7, footnote b), which, when
greater than 3, indicates different codon usage patterns.
D2 values of <3.0 are consistent with a common
origin for the genes (24). We largely limited our analysis
to sequences of >1,000 bp since we observed that
D2 increased when the sequence was small.
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The D2 values, 0.98 to 1.31, indicated that Tn21 merA, Tn501 merA, and Tn501 orf2 have similar codon usage patterns to Tn21 urf2M (Table 7). Higher D2 values (3.21 and 3.61) indicated that Tn21 tnpA and Tn501 tnpA have dissimilar codon usage patterns compared to Tn21 urf2M. Codon usage in each of the two ORFs which comprise the putative Tn21 urf2M (tnpM and urf2) shows that each is as distant from tnpA and as close to merA as is the putative composite gene; thus, by the D2 statistic, neither component gene is related to tnpA or to merA any differently than the putative fused gene. We also noted a surprisingly low D2 value of 1.13 between one of the genes which encodes the Y protein CY02B10.18C (Mycobacterium tuberculosis) and Tn21 urf2M. On the basis of these comparisons, Tn21 urf2M is more likely to have been associated longer with the mer genes than with the tnp genes, although its function in mercury resistance and its relationship to the Y proteins is unknown. An alternative hypothesis is that the origins of these ORFs cannot be discerned by codon usage comparisons because they are nonfunctional and therefore are freer to drift than is a functional gene.
IN2 INTEGRON
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Integrons are a major vehicle for the spread of multiple-antibiotic resistance, and for class 1 integrons, this has been aided by the piggybacking of integrons on other transposons as in Tn21 and its relatives. Integrons provide the cassette-associated resistance genes with two advantages: a "built-in" expression system and ready mobility. Since the promoters located in the 5'-conserved sequence (5'-CS) of the integron (upstream of the inserted cassette) are functional in a wide range of bacteria, the integron can effect the coexpression of several cassette-associated antibiotic resistance genes (11). Cassette-associated resistance genes also harness several mechanisms for their dispersal. Not only are cassettes themselves mobile (10), but also the integrons into which they incorporate are transposable (5). Finally, integrons often occur in plasmids, many of which have broad host range, assisting interspecies spread (16, 81, 104). Integrons and gene cassettes have been reviewed elsewhere (34, 35, 80, 81).
The integron found in Tn21 is a class 1 integron, designated In2 (104), that includes one integrated gene cassette, the aadA1 cassette. At 11 kb, In2 accounts for over half of the total length of Tn21. In2 is flanked by imperfect inverted repeats of 25 bp (IRi and IRj) and bounded by a 5-bp direct duplication of the target sequence (5, 7), indicating that it has transposed into an ancestral tnp-mer transposon to create Tn21. In2 does not include a complete set of transposition (tni) genes and cannot transpose itself (5). However, movement of In2 has occurred, presumably by using transposition proteins supplied in trans, because close relatives of In2 are found in other independent locations (5).
In2 is a composite element that contains a single cassette and two insertion sequences (ISs). The backbone of In2 consists of three distinct regions: 5'-CS, the 3'-conserved segment (3'-CS), and vestiges of the tni transposition gene module (Fig. 2). The 5'-CS and 3'-CS lie on either side of the cassette insertion point, which in In2 is occupied only by the aadA1 cassette. A remnant of the tni module is located to the right of two IS elements, IS1326 and IS1353. One or more deletions originating at the right boundary of IS1326 may have eliminated most of the tni genes. Similarly, a deletion originating at the left end of IS1326 has removed part of the 3'-CS (5). IS1353, which is located within IS1326, is presumed to have been acquired after the integron moved into Tn21, because close relatives of Tn21, e.g., Tn2411, that do not contain IS1353 are known (5, 28). The aadA1 cassette is also found in Tn2411 and may have been present in the In2 progenitor that inserted into the tnp-mer transposon. These six regions are described in detail below.
5'-Conserved Segment
The 5'-CS or intI module of class 1 integrons extends from the left IR, designated IRi, to the boundary of the first integrated cassette (Fig. 2). The 5'-CS includes three repeats at its left end that are predicted to bind the tni transposase (79) (described in more detail below): the intI1 gene, encoding the class 1 integrase; the promoter regions for the intI1 and aadA1 genes; and the bulk of the attI1 site, the IntI1-specific recombination site into which cassettes are inserted. IntI1 is a member of the integrase family of site-specific recombinases (14, 26, 74) and catalyzes recombination between various pairs of recombination sites (59-be [see below] × 59-be, 59-be × attI1, and attI1 × attI1) in experimental conduction assays (32, 38, 60, 61, 82, 105). IntI1 also catalyzes the integration of additional gene cassettes at attI1 (10) and both the excision and rearrangement of gene cassettes (12, 13). Experimentally, the attI1 site consists of at least 34 bp but no more than 64 bp of the 5'-CS and includes 6 to 10 bp at the first adjacent cassette (Fig. 4) (82), although a shorter length has recently been claimed (38). There are four IntI1 binding sites in attI1: two sites appear to consist of a simple integrase recombination site made up of a pair of inversely oriented IntI1-binding sites and two additional IntI1-binding sites (DR1 and DR2) that enhance the efficiency of the simple recombination site (Fig. 4) (14, 25).
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Integrons also include a promoter, Pc (formerly known as
Pant or P1), that directs transcription of the
cassette-borne gene(s) (Fig. 4). The sequences of the 5'-CS of class 1 integrons found in several different locations are >99% identical.
The most frequent differences between the sequences of the 5'-CS from
different integrons occur within the 10 or 35 regions of the
Pc promoter (104), giving rise to variants with
different strengths (9, 11, 55); the variant of
Pc in In2 is the weakest. However, the 5'-CS of In2
contains a unique insertion of three G residues (bases 5278 to 5280 [Table 5]; bold G's in Fig. 4) that increases the spacing between a
distinct set of potential 10 and 35 hexamers from 14 to 17 bp,
thereby creating a second promoter, P2, which is more efficient than
Pc (11, 55). P2 is a secondary promoter found
only in In2 and close relatives. Constitutive transcripts from both
Pc and P2 can be detected (11); there is no
information on whether either is subject to regulation by other factors.
aadA1 Cassette
In2 includes a single gene cassette containing the aadA1 gene, which determines resistance to streptomycin and spectinomycin. The AAD(3") protein is an aminoglycoside adenylytransferase that inactivates these antibiotics by adding an adenyl or other nucleotidyl group. The cassette also contains an IntI1-specific recombination site, the aadA1 59-base element (59-be; also called attC) located downstream of the gene (Fig. 5). The aadA1 cassette thus has the features typical of gene cassettes, i.e., a gene and a 59-be. The aadA1 cassette was presumably incorporated into In2 by IntI1-mediated recombination between the attI1 site and the 59-be in a free circular aadA1 cassette. Experimental evidence for the free circular intermediate and for cassette integration has been reviewed extensively elsewhere (34, 35, 80).
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The aadA1 cassette is organized compactly (Fig. 5). The first possible in-frame ATG codon for aadA1 is only 8 bp from the cassette boundary but is not preceded by a consensus ribosome binding site within the cassette. Alternatively, translation of aadA1 may initiate at a GTG codon, 12 bp downstream, which is preceded by a ribosome binding site. Translation of the aadA2 gene in a related cassette is initiated in this manner (3). The 59-be of the aadA1 cassette lies only 1 bp from the termination codon of the gene.
In the aadA1 cassette, the 59-be is actually 60 bp long and has features common to this family of recombination sites (13, 32, 105). Since the 59-be, of the free circular cassette form, is separated into two parts by the recombination crossover, the 59-be immediately downstream from aadA1 in In2 actually includes 54 bp of the aadA1 59-be (from the circular cassette form) and at least 6 bp (lowercase in Fig. 5) of the adjacent module, which is the 3'-CS of In2. This composite 59-be is called the aadA1/qacE 59-be. The terminal 6 bp of the aadA1 59-be in the circular cassette form lie at the beginning of the integrated aadA1 cassette and constitute part of the composite attI1/aadA1 recombination site of In2. The outer 25 bp of all 59-be are relatively highly conserved (13, 105). Within each 25-bp consensus region is a simple site configuration (1L-2L and 2R-1R [Fig. 5]), as found with other integrase recognition sites, and each simple site includes a pair of inversely oriented 7-bp core sites. Only 8 base of the composite core sites are completely conserved: three each in 1L and 1R (ACC and GTT) and one each in 2L and 2R (A and T) in all 59-be (105).
3'-Conserved Segment
In early studies of class 1 integrons, the 3'-CS was defined as a
conserved region containing three ORFs (qacE
1,
sul1, and orf5) located to the right of the different
cassette arrays found in various integrons (Fig. 2) (104).
More recent studies (5, 33) have revealed that the length of
the 3'-CS region is variable and that some integrons have additional
sequence (orf6 or portions of orf6) downstream of orf5. However, not
all class 1 integrons have this region (Fig.
6); e.g., Tn402, also recently
called Tn5090 (79), does not have a 3'-CS region.
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The qacE gene encodes an inner membrane protein with four
transmembrane segments and determines resistance to quaternary ammonium compounds (antiseptics and disinfectants) by an efflux mechanism (71, 88). The last 66 bp of qacE1 (encoding
115 aa) differs from the complete qacE gene (encoding 110 aa); the qacE1 gene confers only marginal resistance to
quaternary ammonium compounds (75). The sul1 gene
(formerly sulI) encodes a sulfonamide-resistant dihydropteroate synthase (279 aa), which can replace the normal bacterial enzyme targeted by this group of drugs (111). The
function of orf5 is not known; however, the predicted protein is 38%
identical and 47% similar to a puromycin
N-acetyltransferase (gi 1346911) of Streptomyces
alboniger and is 36% identical and 50% similar to a putative
acetyltransferase (gi 3449263) of Streptomyces coelicolor (121). Although in In2, transcription originating from
Pc or P2 in the 5'-CS is likely to extend into the 3'-CS,
affording expression at these three 3'-CS genes, a weak promoter that
is sufficient for expression of sulfonamide resistance has also been identified upstream of the qacE1 gene (30).
In Tn402, the qacE gene is associated with a
59-be and hence is part of a mobile cassette (81), whereas
qacE1 is not mobile. The sul1 and adjacent
sequence may also have originally been part of cassettes which
integrated at attI1 and subsequently became immobilized by
loss of their adjacent 59-be recombination sites (Fig. 6) (5,
104). Thus, the 3'-CS appears to contain vestiges of the earliest
insertion events. The presence of the sul1 gene would
explain the wide distribution of integrons containing this region,
since sulfonamides were the first widely used antimicrobial agents.
tni Transposition Module
Of the class 1 integrons, where sufficient sequence is available, only Tn402 (Fig. 6) carries the full complement of four tni genes (5, 79), believed to encode transposition functions on the basis of their similarity to the tni genes of Tn5053 (Fig. 3) (48). The tniA, tniB, and tniQ genes of Tn5053 are required for transposition, and the fourth gene, tniR, encodes a resolvase which resolves the cointegrates as does TnpR of Tn21 (48). In In2, only one complete gene, tniA, and a truncated version of the tniB gene are present. All class 1 integrons, including Tn402, have complex ends (79). Both ends have three copies of a 19-bp sequence, the outermost of which overlaps the terminal 25-bp IRs. By analogy to Tn7, these three 19-bp repeats are believed to function as transposase binding sites, although the identity of the Tni protein involved is not known.
IS1326 Insertion Sequence
The insertion sequence IS1326 has terminal 26-bp IRs
and includes two ORFs that overlap by 14 bp (5). These ORFs
have been designated istA (1,524 bp) and istB
(786 bp) due to the similarity of their predicted products to IstA and
IstB, required for transposition in IS21 (83).
IstA has a DD(45)E transposase motif and a helix-turn-helix motif, and
IstB has a distinctive set of nucleoside triphosphate binding domains
(5). These two genes have share a common promoter upstream
of istA. However, in In2, IS1353 has inserted
between the 10 and 35 promoter regions of IS1326, and
thus istAB may not be expressed. IS1326 also
occurs in other integrons, e.g., integrons In0 and In5 in plasmids pVS1
and pSCH884, respectively (5).
IS1353 Insertion Sequence
The acquisition of IS1353 by In2 appears to be a recent event that occurred after the movement of the In2 to its present location in Tn21 (5). IS1353 is a member of the IS3 family (5) and has the characteristic 5'-TG and CA-3' at the outer ends of its terminal 12-bp IRs. IS1353 is flanked by a direct duplication of 2 bp of the target sequence. It contains two ORFs, orfA and orfB, transcribed in the opposite direction from istA and istB of IS1326. A potential promoter for orfA and orfB lies 24 bp upstream of the putative OrfA translational start. OrfB has a DD(35)E transposase motif similar to other transposases of the IS3 family (23). A potential frameshift motif, A6G, and a predicted mRNA stem-loop are present where the orfA and orfB reading frames overlap, suggesting that (like other IS3 relatives, IS911 and IS150), three polypeptides, OrfA, OrfB, and a fusion protein (OrfAB) that is the actual transposase, may be produced (78). The initiation codon of OrfB has yet to be determined; it may be at the ATT codon 3 bp upstream of the A6G motif (as seen in IS911) or at the ATG codon 6 bp downstream of the A6G motif.
TN21 EVOLUTION
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Transposons are important for bacterial evolution and adaptation because they carry traits that can be useful for the host cell in varying environments; Tn21 provides its host cell with both antibiotic and mercury resistance determinants. The Tn21 subgroup of transposons is phylogenetically identified on the basis of tnp genes, res sites, and IR ends, but its members vary considerably in the number and types of additional genes (29, 58) they carry. Moreover, some transposons in this subgroup do not carry either a mer region or any resistance genes. The ubiquity and variety of elements in the Tn21 subgroup is the result of several recombination processes (29).
Two characteristics of the transposition machinery of the Tn21 subgroup of transposons foster their ready association with many different genetic loci. The first of these characteristics is that both the resolvase and the transposase have rather broad substrate specificities for the DNA sites which are their substrates. For example, the Tn21 TnpA transposase recognizes several different IR sequences and can also mediate one-ended transposition to generate novel joint molecules (29). In addition, the various TnpR resolvases act on each other's res sites, yielding distinct rearrangements of these transposons (29). The second characteristic of the Tn21 subgroup which enhances their variety is the placement of the res site to one side of tnpA and tnpR (Fig. 2) rather than between them (as found in the Tn3 transposon family). This arrangement minimizes the segregation of tnpR and tnpA which might otherwise occur in aberrant resolution events and results in a relatively stable resolvase-transposase "module." In addition to these properties of the Tn21 subgroup, two or more Tn21-like elements are often found in the same bacterial strain, typically on large conjugative plasmids, where host-mediated homologous recombination can also contribute to their reassortment (59).
Moreover, when an integron is present, two IntI1-mediated, RecA-independent, site-specific recombination processes occur: (i) insertion, rearrangement, or excision of antibiotic resistance gene cassettes (10, 12, 13) and/or (ii) formation and resolution of cointegrates. Both processes involve recombination between various pairs of specific recombination sites (59-be × 59-be, 59-be × attI1, and attI1 × attI1) (32, 38, 60, 61, 82, 105), thus enabling the rapid development of new arrays of antibiotic resistance genes (Fig. 6). Further variation results from the acquisition of insertion sequences, transposons, and integrons and subsequent deletions arising at their ends and mediated by them (5).
Model for Tn21 Evolution
Several transposons, considered to be very close relatives of Tn21, have nearly identical DNA sequences or restriction maps in the tnp and mer regions but differ in that they carry no or different antibiotic resistance genes. Tanaka et al. (112) first proposed that those Tn21-like transposons which confer multiple antibiotic resistance had descended from an ancestral mercury resistance transposon like Tn501 by successive insertions of antibiotic resistances and/or insertion sequences. Their restriction endonuclease analysis indicated similarity between the mer and the tnp regions of Tn2613, which lacks antibiotic resistance genes, and the corresponding regions of Tn2608, which has a 6.3-kb insertion between the mer and tnp regions and has also gained streptomycin and sulfonamide resistances. These observations suggested that Tn2613 might reasonably be considered the predecessor of Tn2608. However, Tn21 itself has a slightly different restriction map in the Tn21 IRmer and in the tnpM regions from those of both Tn2613 and Tn2608, suggesting that neither of these transposons was the immediate predecessor of Tn21.
A more recent model for the evolution of Tn21 and other family members (5) is based on restriction maps, heteroduplex analyses, and sequence data for a larger group of these transposons (19, 53, 63, 94, 110, 113, 117, 119, 122, 123). In this analysis, those considered members of the family are similar to Tn21 in carrying the same tnpRA transposition genes and an integron in the same position as In2. They may or may not carry the complete mer locus, and they also differ from Tn21 in either the identity or number of gene cassettes in the integron or by the acquisition or loss of other IS elements or transposons. For example, the original Tn21, isolated in Japan, includes a 1.6-kb region corresponding to IS1353 that is not present in related isolates from Germany (29), which suggests that Tn21 acquired IS1353 after the global spread of an ancestor such as Tn2411 that does not contain this IS (5).
Brown et al. (5) proposed that Tn2411 arose from
a hypothetical ancestor called Tn21, which lacks an
integron but contains the mer operon (Fig. 6). In
Tn21, urf2M would be present (as seen in orf2 and urf2
adjacent to mer operons in Tn501
[6] and pPB [84], respectively [Fig.
3]). The ancestor of In2 (without IS1353) inserted into
Tn21, perhaps via a transposition event catalyzed in
trans by another transposon with a complete set of tni transposition genes. The alternative, i.e., that the In2
ancestor might have been complete and later lost its tni
genes by a deletion event occurring on or after insertion of
IS1353, seems unlikely since integrons with very similar
organization to In2 are found in other locations (5).
Subsequently, transposon Tn2411 became widely distributed, experiencing integration, excision, or exchange of gene cassettes, insertion of transposons or insertion sequences, and IS-mediated deletions or excisions (Fig. 6), which have given rise to the examples of this group described so far (19, 53, 63, 94, 110, 119, 122, 123) and probably many others.
Model for In2 Evolution
The In2 integron is believed to have been a highly evolved element
(Fig. 6) before it integrated into Tn21. Brown et al. (5) have proposed that the central components of In2 evolved from a progenitor, similar to Tn402, which had experienced
several genetic events prior to insertion into Tn21.
These genetic events would include the creation of the 3'-CS via the
integration of qacE, as well as sul1, and other
putative cassettes and subsequent events to immobilize them. After the
insertion of IS1326, this IS caused the partial deletion of
the adjacent 3'-CS and tni module. The insertion of
IS1353 occurred after the integron moved into Tn21 and is likely to be the latest event in the creation
of both In2 and Tn21.
Codon Usage Comparisons
Tn21 can be viewed as an assemblage of genes captured
by transposition genes: the tnp genes acquired the
mer operon, and the tni genes acquired the
integrase system. After these two independent events, the integron
progenitor, itself an assemblage of genes captured by either the
tni module or the integrase module, inserted into
Tn21, followed by insertion of IS1353 (Fig.
6). Some hints about the variety of sources of these many components is
given by their codon usage patterns.
Codon usage comparisons of Tn21 genes point to significant
diversity in their origins (Table 8). Codon usage comparisons of
merA and urf2M reveal low D2 values
with respect to each other but not with respect to other integron or
tnp genes, with the exception of orfAB of IS1353. Codon usage in aadA1, as in the majority of genes found in
integrated cassettes (2), is quite dissimilar to that in
other genes within the integron, presumably reflecting diverse origins
of the cassette-associated genes. In Tn21, the exception to
this appears to be the low D2 values between
aadA1 and istAB (IS1326) and orfAB
(IS1353). High D2 values are also
observed between qacE1 (a former cassette) and all other
Tn21 genes compared with it. Codon usage comparisons of
genes within the integron revealed low D2 values
between intI1, sul1, and tniA,
suggesting that these genes originated from closely related
microorganisms which are different from E. coli or
Pseudomonas aeruginosa (2, 79). This observation supports the view that sul1 was integrated early in the
evolution of class 1 integrons (104). Comparison of codon
usage in Tn402 genes revealed similar low
D2 values (0.81) between int and
tniA as for those genes in Tn21 and high
D2 (9.27 to 6.98) values between qacE
and other genes within this integron (79). The low
D2 values between most of the Tn21
genes and the orfAB genes in IS1353 suggest that perhaps
IS1353 was acquired while Tn21 was in a host with
codon utilization similar to that of the ancestral host of
Tn21.
TN21 SAILS THE WORLD
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The Tn21 family is widely distributed in both clinical and environmental isolates of gram-negative bacteria. All characterized examples of the Tn21 family have been found on large conjugative plasmids. Although bacterial conjugation was once believed to be restricted in host range, it now appears that this mechanism of transfer permits genetic exchange between many different bacterial genera in nature (16, 50).
Environmental Occurrences
Pearson et al. observed the widespread distribution of Tn21- and Tn501-related tnpA and tnpR sequences in soil bacteria from three sites (two mercury-polluted sites and one pristine site); 20 of 30 isolates hybridized to transposase and resolvase gene probes (76). They observed extensive recombination between different transposition genes and reassortment of the mer and the transposition gene regions. Further evidence for widespread distribution includes a recent report of the occurrence of Tn21-, Tn501-, and Tn3-related tnpA sequences in total bacterial DNA from the marine environment (15). The Tn21 tnpA sequence occurred once per 103 or 104 bacteria.
Clinical Occurrences
Apart from the above environmental isolates, Tn21 carriage of integrons and integrated cassette-associated resistance genes in gram-negative pathogens is also well documented (32, 53, 80). The Tn21 family encodes resistances against both older and newer antibiotics. Strains of bacteria resistant to streptomycin, an antibiotic rarely used medically in the past 30 years but still extensively used in animal husbandry, are frequently found (68). In a 1995 study, over half (53%) of 49 clinical isolates with transferable resistance to aminoglycosides carried integrons with aadA1 (25%) or aacA4 (75%) gene cassettes (92). In an earlier (1992) study, 807 unselected gram-negative clinical isolates were screened to determine the distribution of the integron and Tn21 transposition genes (128). A total of 19% of the isolates carried some part of the tnpA tnpR, or intI1 gene and 8% of the isolates had all of the genes, although linkage of tnp genes and integrons was not demonstrated. Besides complete Tn21-like transposons, a great variety of defective transposons were observed in many genera of bacteria (128).
Tn21 and Tn21-like transposons with integrons have also been observed in primate intestinal bacteria that were challenged with Hg(II) released from dental amalgams (108). There was a strong association of multiple-antibiotic resistance with two of the most abundant phylogenetic types of Hg resistance locus (locus 1 and locus 4) in these bacteria (58, 118). Using PCR, we have established (Fig. 7) that mer locus 1 carries a In2-like integron and that some examples of mer locus 4 carry a class 1 integron similar to In4 in Tn1696 (119). In both mer locus types, the adjacent integrons carry from one to four antibiotic resistance genes. Hg exposure experienced by the fecal flora of these animals led to enrichment for strains carrying Hg resistance loci closely linked to integron multiple-antibiotic resistant transposons.
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The causes of the dissemination of the Tn21 family of transposons are presently unknown but may be due to the chance association of the integron and mer at a time when the rich ecosystem of the human intestinal microflora was experiencing increasing antibiotic usage coinciding with exposure to Hg due to its use in the treatment of syphilis and in amalgam dental restorations.
CONCLUDING REMARKS
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Tn21 and its relatives are major agents in the dissemination of mercury resistance and antibiotic resistance genes in gram-negative bacteria. Understanding the molecular processes involved in the accumulation and exchange of resistance genes by these integron-carrying transposons will inform efforts to control the spread of these genes as well as others which will arise in response to newer antibiotics. The regulation of antibiotic resistance gene cassette movement and stability, the factors that influence the recombination processes in the transposon, and the question whether there are environmental selection pressures other than antibiotics that contribute to their spread are subjects of intense study in many laboratories worldwide. Like mariners of old, Tn21 has left its kin in many ports and picked up barnacles along the way. As others of its family come to light, we expect that there will be answers to many of the questions posed above. We encourage others working on similar complex transposable elements and plasmids to compile and deposit their sequences. Such data will be essential to understanding the still-evolving relationships between the ubiquitous, peripatetic "floating" genome and the more constant cellular chromosomes.
ACKNOWLEDGMENTS
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We gratefully acknowledge the cheerful and competent assistance of Alice L. Watson for sequence entry into GenBank; GCG advice from Michael Weise; and comments on the manuscript by Nigel Brown, Paul H. Roy, Jim Shapiro, and an anonymous reviewer.
This project was partially supported by grants from NIH (GM28211), the Wallace Research Foundation, and the International Academy of Oral Medicine and Toxicology to A.O.S. and grants from the NHIMRC to R.M.H.
FOOTNOTES
* Corresponding author. Mailing address: Department of Microbiology, The University of Georgia, Athens, GA 30602-2605. Phone: (706) 542-2669. Fax: (706) 542-6140. E-mail: Summers{at}ARCHES.UGA.EDU.
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Perichon, B., Bogaerts, P., Lambert, T., Frangeul, L., Courvalin, P., Galimand, M.
(2008). Sequence of Conjugative Plasmid pIP1206 Mediating Resistance to Aminoglycosides by 16S rRNA Methylation and to Hydrophilic Fluoroquinolones by Efflux. Antimicrob. Agents Chemother.
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Revilla, C., Garcillan-Barcia, M. P., Fernandez-Lopez, R., Thomson, N. R., Sanders, M., Cheung, M., Thomas, C. M., de la Cruz, F.
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Martinez, N., Mendoza, M. C., Rodriguez, I., Soto, S., Bances, M., Rodicio, M. R.
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Holt, K. E., Thomson, N. R., Wain, J., Phan, M. D., Nair, S., Hasan, R., Bhutta, Z. A., Quail, M. A., Norbertczak, H., Walker, D., Dougan, G., Parkhill, J.
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Sekiguchi, J.-I., Asagi, T., Miyoshi-Akiyama, T., Kasai, A., Mizuguchi, Y., Araake, M., Fujino, T., Kikuchi, H., Sasaki, S., Watari, H., Kojima, T., Miki, H., Kanemitsu, K., Kunishima, H., Kikuchi, Y., Kaku, M., Yoshikura, H., Kuratsuji, T., Kirikae, T.
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Szczepanowski, R., Krahn, I., Bohn, N., Puhler, A., Schluter, A.
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Levings, R. S., Partridge, S. R., Djordjevic, S. P., Hall, R. M.
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Rodriguez, I., Martin, M. C., Mendoza, M. C., Rodicio, M. R.
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Khan, A. A., Cheng, C.-M., Van, K. T., West, C. S., Nawaz, M. S., Khan, S. A.
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Stokes, H. W., Nesbo, C. L., Holley, M., Bahl, M. I., Gillings, M. R., Boucher, Y.
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Poole, T. L., McReynolds, J. L., Edrington, T. S., Byrd, J. A., Callaway, T. R., Nisbet, D. J.
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Toleman, M. A., Bennett, P. M., Walsh, T. R.
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Rodriguez, I., Rodicio, M. R., Mendoza, M. C., Cruz Martin, M.
(2006). Large Conjugative Plasmids from Clinical Strains of Salmonella enterica Serovar Virchow Contain a Class 2 Integron in Addition to Class 1 Integrons and Several Non-Integron-Associated Drug Resistance Determinants. Antimicrob. Agents Chemother.
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Tuffin, I. M., Hector, S. B., Deane, S. M., Rawlings, D. E.
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Valverde, A., Canton, R., Galan, J. C., Nordmann, P., Baquero, F., Coque, T. M.
(2006). In117, an Unusual In0-Like Class 1 Integron Containing CR1 and blaCTX-M-2 and Associated with a Tn21-Like Element. Antimicrob. Agents Chemother.
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Poole, T. L., Callaway, T. R., Bischoff, K. M., Warnes, C. E., Nisbet, D. J.
(2006). Macrolide inactivation gene cluster mphA-mrx-mphR adjacent to a class 1 integron in Aeromonas hydrophila isolated from a diarrhoeic pig in Oklahoma. J Antimicrob Chemother
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Miko, A., Pries, K., Schroeter, A., Helmuth, R.
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Johnson, T. J., Siek, K. E., Johnson, S. J., Nolan, L. K.
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Gestal, A. M., Stokes, H. W., Partridge, S. R., Hall, R. M.
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Boerlin, P., Travis, R., Gyles, C. L., Reid-Smith, R., Heather Lim, N. J., Nicholson, V., McEwen, S. A., Friendship, R., Archambault, M.
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Coram, N. J., van Zyl, L. J., Rawlings, D. E.
(2005). Isolation, Sequence Analysis, and Comparison of Two Plasmids (28 and 29 Kilobases) from the Biomining Bacterium Leptospirillum ferrooxidans ATCC 49879. Appl. Environ. Microbiol.
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Sekiguchi, J.-i., Asagi, T., Miyoshi-Akiyama, T., Fujino, T., Kobayashi, I., Morita, K., Kikuchi, Y., Kuratsuji, T., Kirikae, T.
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Tuffin, I. M., de Groot, P., Deane, S. M., Rawlings, D. E.
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Haines, A. S., Jones, K., Cheung, M., Thomas, C. M.
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Kehrenberg, C., Catry, B., Haesebrouck, F., de Kruif, A., Schwarz, S.
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Coleman, N. V., Holmes, A. J.
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Szczepanowski, R., Braun, S., Riedel, V., Schneiker, S., Krahn, I., Puhler, A., Schluter, A.
(2005). The 120 592 bp IncF plasmid pRSB107 isolated from a sewage-treatment plant encodes nine different antibiotic-resistance determinants, two iron-acquisition systems and other putative virulence-associated functions. Microbiology
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Riccio, M. L., Pallecchi, L., Docquier, J.-D., Cresti, S., Catania, M. R., Pagani, L., Lagatolla, C., Cornaglia, G., Fontana, R., Rossolini, G. M.
(2005). Clonal Relatedness and Conserved Integron Structures in Epidemiologically Unrelated Pseudomonas aeruginosa Strains Producing the VIM-1 Metallo-{beta}-Lactamase from Different Italian Hospitals. Antimicrob. Agents Chemother.
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Poirel, L., Lartigue, M.-F., Decousser, J.-W., Nordmann, P.
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Lee, K., Yong, D., Yum, J. H., Lim, Y. S., Kim, H. S., Lee, B. K., Chong, Y.
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Schleinitz, K. M., Kleinsteuber, S., Vallaeys, T., Babel, W.
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Nandi, S., Maurer, J. J., Hofacre, C., Summers, A. O.
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Kholodii, G., Mindlin, S., Gorlenko, Z., Petrova, M., Hobman, J., Nikiforov, V.
(2004). Translocation of transposition-deficient (TndPKLH2-like) transposons in the natural environment: mechanistic insights from the study of adjacent DNA sequences. Microbiology
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(2003). The IS1111 Family Members IS4321 and IS5075 Have Subterminal Inverted Repeats and Target the Terminal Inverted Repeats of Tn21 Family Transposons. J. Bacteriol.
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Wain, J., Diem Nga, L. T., Kidgell, C., James, K., Fortune, S., Song Diep, T., Ali, T., O Gaora, P., Parry, C., Parkhill, J., Farrar, J., White, N. J., Dougan, G.
(2003). Molecular Analysis of incHI1 Antimicrobial Resistance Plasmids from Salmonella Serovar Typhi Strains Associated with Typhoid Fever. Antimicrob. Agents Chemother.
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Carattoli, A., Filetici, E., Villa, L., Dionisi, A. M., Ricci, A., Luzzi, I.
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