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Antimicrobial Agents and Chemotherapy, March 1999, p. 686-689, Vol. 43, No. 3
Eijkman-Winkler Institute for Clinical
Microbiology, University Hospital of Utrecht, 3584CX Utrecht, The
Netherlands
Received 22 June 1998/Returned for modification 15 October
1998/Accepted 22 December 1998
Three sizes of inserted regions of DNA (800, 1,000, and 1,500 bp)
were shown to be common among class I integrons in unrelated clinical
isolates of Enterobacteriaceae from different European hospitals. Sequencing showed that 800-bp inserted regions comprised identical sequences including aacA4, that 1,000-bp inserted
regions included aadA, and that 1,500-bp inserted regions
included dfrI and aadA1, irrespective of host
species and geographic origin. In addition promoter sequences were
mostly identical for each size class. These data suggest that inserted
gene cassettes and promoter regions of integrons are conserved and
stable, with resistance genes transferred more often as part of the
entire integron structure than as individual gene cassettes.
Integrons are genetic structures
capable of integrating or mobilizing individual gene cassettes encoding
antibiotic resistance determinants. Since integrons are carried on
plasmids and transposons, a strong antibiotic selective pressure can
potentially result in the mobilization and dissemination of antibiotic
resistance genes (4). Previous studies have demonstrated
that these integron structures occur widely among
Enterobacteriaceae species in European hospitals and are
significantly associated with resistance to multiple classes of
antibacterial compounds (5, 10).
Integrons possess two essential elements located at the 5' conserved
segment (CS) able to mobilize and insert gene cassettes, namely an
int gene encoding a site-specific recombinase belonging to
the integrase family and its associated primary recombination site,
attI (3). Captured genes, most commonly encoding
antibiotic resistance, are part of discrete mobile cassettes which
contain the protein coding region and a recombination site, known as a 59-base element, located at the 3' end of the gene (8, 9). While four types of integrons, each with different int
genes, have been identified to date, most integrons found in clinical enterobacterial isolates are class I integrons.
So far more than 40 different antibiotic resistance genes have been
shown to be carried within class I integrons, alone or in various
combinations, suggesting a high transferability of these genes, which
can be integrated, mobilized, or conserved. Inserted genes are
expressed primarily via a common promoter, P1, located in
the 5' CS. Three versions of P1 are known to exist, with
different combinations of
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Copyright © 1999, American Society for Microbiology. All rights reserved.
Many Class I Integrons Comprise Distinct Stable
Structures Occurring in Different Species of
Enterobacteriaceae Isolated from Widespread Geographic
Regions in Europe
ABSTRACT
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35 and 10 sequences in comparison to
consensus sequences. These are TTGACAN17TAAACT
(a strong promoter), TGGACAN17TAAGCT (a
weak promoter), and TGGACAN17TAAACT (a hybrid promoter) (7, 18). Such sequence changes may be a crude
mechanism of control of gene expression. In addition the insertion of
three guanosine molecules 119 bases downstream of the promoter
P1 creates a downstream secondary weak promoter,
P2, resulting in a second initiation point of
transcription, thus increasing the expression of inserted gene
cassettes (3, 7) (Fig. 1). In
Escherichia coli a strong P1 and a weak
P1 in combination with P2 are six and three
times more efficient than the tac promoter, respectively. Although not yet studied, it is assumed that these promoters behave with a comparable efficiency in other enterobacterial species (7). Genes adjacent to the common promoter P1
are expressed with the highest efficiency, although promoter variety,
plasmid copy number, and the presence of other internal promoters may also affect expression.
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FIG. 1.
The 5' CS regions of class I integrons showing four
different combinations of promoter sequences and inserted gene
cassettes found among isolates studied. Promoter sequences are shown in
bold type and are marked as P1 or P2. Isolates
with an 800-bp region inserted carry a strong P1 promoter
and aacA4 gene and a unique 19-bp inserted sequence shown in
parentheses. Isolates with 1,000-bp inserted regions possess a weak
P1 promoter plus a weak P2 promoter made active
by the insertion of three guanosine residues (underlined) and an
aadA inserted gene cassette. Two groups of isolates with
1,500-bp inserted regions were identified; both have dfrI
and aadA as inserted gene cassettes, but one possesses a
weak P1 promoter and the other possesses a weak
P1 promoter plus a weak P2 promoter made active
by the insertion of three guanosine residues (underlined). The unique
attI site AGTT followed by the inserted resistance gene in
each sequence is shown in italics.
Together, the genetic idiosyncrasies of class I integrons suggest that they are fluid genetic elements capable of rapidly mobilizing or capturing resistance genes in response to environmental pressures. However, a previous study of ours, using a targeted PCR protocol to amplify inserted gene cassettes adjacent to the 5' CS, demonstrated that a few distinct size groups of inserted regions of DNA predominate in bacteria isolated from different European hospitals (10). These most commonly comprised inserted DNA regions of 800, 1,000, and 1,500 bp, presumably consisting of single or multiple gene cassettes. In most bacteria only one integron was detected per isolate, although a few contained two or even three regions of inserted DNA of different sizes, including sizes larger or smaller than the predominant size classes, a fact that is suggestive of multiple integron carriage. These predominantly common sizes suggested at least that inter- and intraspecific gene transfers occur often, by the mobilization of a complete integron structure rather than individual resistance gene cassettes. We hypothesized that integron structures, at least in the predominant size classes, were possibly more stable than had been suggested previously.
In order to test this hypothesis we sequenced the 5' CS promoter regions and gene cassettes, inserted between the 5' CS and a semiconserved downstream 3' region, of integrons of 21 enterobacterial organisms harboring the three most common size groups of inserted DNA regions found. Oligonucleotides and PCR conditions used to amplify integron structures for sequence analyses were those described previously (6). Sequencing reactions on amplicons were performed on both strands with PCR cycle sequencing kits (Perkin-Elmer, Gouda, The Netherlands) according to the manufacturer's instructions. All organisms studied were recent clinical isolates from blood, shown to be unrelated by virtue of random amplified polymorphic DNA typing by a standard procedure (10, 15). Isolates originated in 10 different locations (Düsseldorf and Freiburg, Germany; Warsaw and Lodz, Poland; Seville and Madrid, Spain; Paris, France; Genoa, Italy; Liege, Belgium; and Bristol, United Kingdom) and belonged to six different species (E. coli, Klebsiella oxytoca, Enterobacter cloacae, Enterobacter aerogenes, Proteus mirabilis, and Serratia marcescens).
Sequencing revealed that all isolates containing 800-bp inserted regions (four isolates) comprised aacA4 alone (encoding resistance to tobramycin and amikacin), those with 1,000-bp inserted regions (nine isolates) all comprised aadA (encoding resistance to spectinomycin-streptomycin), and those with 1,500-bp inserted regions (eight isolates) comprised dfrI and aadA (encoding resistance to trimethoprim and spectinomycin-streptomycin). All isolates with the 800-bp inserted region carried aacA4, downstream of a so-called strong P1 promoter, and a unique 19-bp region in the attachment sequence of the 5' CS (Fig. 1). Two of these isolates, both from Liege, also carried two additional detectable inserted regions of unique sizes (>2,000 bp) which were not studied. All aadA genes contained within 1,000-bp inserted regions were downstream of weak P1 promoters, with the exception of one E. cloacae isolate from Italy. In this isolate the aadA gene was also present but was linked to a 5' CS region different from the 5' CS region upstream of the aacA4 gene characteristic of the 800-bp insert, in that no 19-bp repeat sequence was present. This is suggestive of an identical integron structure mutated within the promoter region, changing the P1 promoter type from weak to strong. Four of the eight 1,500-bp inserted regions comprising dfrI and aadA genes possessed weak P1 promoters, with all others having a weak P1 promoter plus a weak P2 promoter downstream (Fig. 1). Thus, in every isolate we studied, the nucleic acid sequences of the promoter regions and inserted resistance gene(s) within each inserted region size class were identical, irrespective of the geographic source and species (except for those with 1,500-bp inserted regions which formed two distinct promoter-type groups, each with identical inserted gene sequences).
If the mobilization and subsequent integration of resistance gene
cassettes were common occurrences in response to changing antibiotic
selective pressures we would perhaps expect to find considerable
variation in the combinations of inserted gene cassettes and promoter
types. However, our results refute this hypothesis, as we show that the
most commonly found combinations of resistance genes and promoter
sequences are highly conserved in different species isolated in
different European hospitals (Table 1). A similar conservation of promoter and cassette combination was previously reported among dihydrofolate reductase genes carried on
unrelated plasmids of diverse origins (20, 21). Rather than
suggesting that integrons and the inserted genes they contain are
highly mobile and changeable structures recently evolved in the
hospital environment, this suggests that they are evolutionarily older
and more stable, perhaps originating from a common source. A recent
report demonstrated that aadA is commonly carried in integrons in Enterobacteriaceae organisms in a London
hospital, despite the limited use of streptomycin (2).
Although many different resistance genes have been reportedly carried
within integrons and the role of the integrase in the insertion and
excision of gene cassettes has been clearly shown (14), the
common occurrence of conserved integron structures in different species
strongly suggests that the intra- or interspecific transfer of the
entire integron (presumably via plasmids or transposons) is a more
frequent event than single gene mobilization or integration via the
integrase. However, our studies do not preclude the possibility that
other integrons harbor more mobile inserted gene cassette combinations.
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Furthermore, we attempted to induce changes within the integron structure in vitro. Clinical isolates representative of each of the species studied that harbored integrons with 800-bp inserted regions (aadA plus a weak P1 promoter and a P2 promoter) or 1,500-bp inserted regions (dfrI-aadA genes plus a weak P1 promoter) were passaged in triplicate, in Mueller-Hinton broth or Mueller-Hinton agar plates with doubling dilutions (1 to 1,024 mg/liter) of streptomycin, in order to try to induce changes in the P1 promoter region (from weak to strong) or resistance gene order (shift of aadA adjacent to the P1 promoter). Despite several attempts, no colonies for which MICs of streptomycin were increased, compared to the parent strain, were obtained, and subsequent sequencing of the amplified integron from randomly selected overnight colonies was not able to detect nucleotide sequence changes in any of the integrons studied.
Recently the finding of class IV integrons has demonstrated that these genetic structures function in bacterial genome evolution (11), probably through the fixed integration of genes which confer selective advantages at secondary sites. This role for antibiotic resistance cassettes has been previously proposed (14) but has not been addressed with sample isolates that are diverse with respect to species and geographic origin as we have done. Our data show a high frequency of particular combinations of antibiotic resistance genes, associated with distinct promoter sequences circulating in European hospitals and seemingly transferred both inter- and intraspecifically, and thus tend to support this theory.
In conclusion, class I integrons containing the most commonly found insert sizes seem not to be fluid genetic elements, frequently sequestering and mobilizing resistance genes. Rather, they seem often to comprise conserved stable structures which are mobilized en masse, often concomitantly with other genetically associated resistance determinants. The decreased susceptibility or resistance to antibiotics provided by integrons and their association with other episomal elements also involved in antimicrobial resistance (10, 12, 13, 22) can explain their widespread occurrence within the nosocomial environment.
Nucleotide sequence accession numbers. Promoter sequences shown in Fig. 1 are identical to those first identified by Stokes and Hall (18), appearing in the EMBL and GenBank databases as accession no. X04555, strong P1 promoter (1); X12868, weak P2 promoter (19); and X12618, weak P1 promoter plus weak P2 promoter (16, 17).
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ACKNOWLEDGMENTS |
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We thank Edith Peters and Nienke Boenink for help during this study and all hospitals referring isolates.
This study was supported by European Union grant ERBCHRCT940554.
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FOOTNOTES |
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* Corresponding author. Present address: MRL Pharmaceutical Services, Den Brielstraat 11, 3554XD Utrecht, The Netherlands. Phone: 31 30 265 1794. Fax: 31 30 265 1784. E-mail: mjones{at}thetsn.com.
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