JAC Advance Access originally published online on November 16, 2006
Journal of Antimicrobial Chemotherapy 2007 59(2):184-190; doi:10.1093/jac/dkl471
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Proteus mirabilis clinical isolate harbouring a new variant of Salmonella genomic island 1 containing the multiple antibiotic resistance region
1 Laboratory of Food Microbiology and Hygiene, Graduate School of Biosphere Science, Hiroshima University Higashi-Hiroshima 739-8528, Japan 2 Department of Microbiology, Faculty of Veterinary Medicine, Kafr El-Sheikh University Kafr El-Sheikh 33516, Egypt 3 Graduate School of Medical Science, Kanazawa University Kanazawa 920-8640, Japan
*Corresponding author. Tel/Fax: +81-82-424-7897; E-mail: tadashis{at}hiroshima-u.ac.jp
Received 4 September 2006; returned 12 October 2006; revised 23 October 2006; accepted 25 October 2006
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Abstract |
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Objectives: A clinical isolate of Proteus mirabilis strain 18306, which displayed the multidrug resistance phenotype of Salmonella genomic island 1 (SGI1), was examined for the presence of this island including its multiple antibiotic resistance genomic region.
Methods: P. mirabilis 18306 was isolated in March 2006 from a patient in Palestine with diabetic foot infection. Antibiotic susceptibility tests and various molecular techniques, including PCR, cloning and DNA sequencing were used for detection and characterization of SGI1 in P. mirabilis 18306.
Results: P. mirabilis 18306 showed the typical multidrug resistance phenotype of SGI1 as it was resistant to ampicillin, chloramphenicol, streptomycin, sulphonamides and tetracycline, in addition to trimethoprim and nalidixic acid. Molecular characterization showed that P. mirabilis 18306 harboured a structure similar to SGI1, except that the aadA2 gene, which confers resistance to streptomycin and spectinomycin, of standard SGI1 had been replaced with dfrA15, which confers resistance to trimethoprim. Furthermore, the nucleotide sequence of the extrachromosomal circular form of SGI1 in P. mirabilis was found to be identical to that of Salmonella Typhimurium DT104. However, PCR results showed that P. mirabilis 18306 was negative for the left and right junctions which represent the integration sites of SGI1 into Salmonella enterica chromosome. Hence, this new variant of SGI1 may be integrated at a different site into the chromosome of P. mirabilis 18306. Tn1826-derived class 2 integron, which carries only two gene cassettes, sat2 and aadA1, was also identified in this strain.
Conclusions: In this study, we identified a new variant SGI1 containing the multiple resistance genomic region in a multidrug-resistant strain of P. mirabilis. This is the first report for SGI1 in a genus other than Salmonella.
Keywords: diabetic foot infections , integrons , multidrug resistance
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Proteus mirabilis is one of the most common Gram-negative pathogens encountered in clinical specimens, and can cause a variety of community- or hospital-acquired infections, including those of the urinary tract, respiratory tract, wounds and burns, bacteraemia, neonatal meningoencephalitis, empyema and osteomyelitis.1 After Escherichia coli, P. mirabilis is the most often isolated member of the Enterobacteriaceae in European clinical microbiology laboratories,2 and it accounts for
3% of nosocomial infections in the United States.3 Foot infections in patients with diabetes mellitus are among the most common bacterial infections encountered in clinical practice, which, once established, progressively worsen and become more difficult to treat.4 Amputation may be needed when infections fail to respond to therapy. The infections are normally polymicrobial, and P. mirabilis is involved as an opportunistic pathogen.4
The term Salmonella genomic island 1 (SGI1) is used to describe a 43 kb island, which has been inserted into the 3' end of the thdF gene in the chromosome of several Salmonella serovars.5 This island contains basically five antibiotic resistance genes, aadA2, sul1, floR (cmlA-like), tet(G) and blaP1 (also named blaPSE-1 or blaCARB-2), that confer resistance to streptomycin and spectinomycin, sulphonamides, chloramphenicol and florfenicol, tetracyclines, and ß-lactam antibiotics, respectively. These antibiotic resistance genes are clustered in a region of 13 kb called the multidrug resistance region (hereafter, MDR region), which is located at the 3' end of SGI1.5 The MDR region of SGI1 represents a complex structure of class 1 integron recently named as In104.6 In104 includes duplications of parts of the integron 5'- and 3'-conserved segments (CSs). Therefore, In104 basically consists of two class 1 integrons, one contains the aadA2 gene cassette and the other contains the blaP1 gene cassettes, while the floR and tet(G) genes lie between these two cassettes.6
Over the last decade, SGI1 has been found to be responsible for a characteristic multidrug resistance pattern associated with an epidemic strain of Salmonella Typhimurium DT104.7 This strain is resistant to ampicillin, chloramphenicol, streptomycin, sulphonamides and tetracycline (resistance profile ACSSuT).5 The epidemic strain of Salmonella Typhimurium DT104 was originally isolated from cattle and humans in the United Kingdom in 1989,8 and then spread pandemically to other countries.7
Later, SGI1 and its ACSSuT resistance profile was characterized in another Salmonella Typhimurium phage type (e.g. DT120)5 and other serovars such as Agona,5 Paratyphi B9 and Meleagridis.10 In Japan, we have detected SGI1 in a multidrug-resistant strain of Salmonella Paratyphi B.11
Over the past few years, SGI1 with variant antibiotic resistance gene clusters (termed variant SGI1) have been described in Salmonella Typhimurium DT104 and Salmonella Agona,12,13 Salmonella Albany14 and Salmonella Newport.15 Recently, SGI1 and its variants have been found to be widely distributed in other Salmonella serovars.6
In 2005, Doublet et al.16 succeeded in conjugally transferring SGI1 from Salmonella enterica donor strains to non-SGI1 S. enterica and E. coli recipient strains, where it integrated into the recipient chromosome in a site-specific manner, therefore, SGI1 can be classified within the group of integrative mobilizable elements (IMEs).17 The genetic elements in this family are excised from the chromosomes of their hosts, transferred to a new host through conjugation, and integrated into the chromosome again. For SGI1, it first forms a circular extrachromosomal intermediate through specific recombination of the left and right ends of the integrated element. Then, chromosomal integration of SGI1 occurs via site-specific recombination of an 18 bp sequence found in the circular form of SGI1, and recombination of a similar 18 bp sequence at the 3' end of the thdF gene in the S. enterica and E. coli chromosomes.16
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Bacterial strains
P. mirabilis 18306 was isolated in March 2006 from a patient in Palestine with diabetic foot infection. The complete biochemical identification of P. mirabilis 18306 was performed with API 20E system (BioMérieux, Marcy-l'Étoile, France). Salmonella Typhimurium DT104 strain J-R2 carrying SGI1 was used as a positive control.18 E. coli TG1 was used as a host for cloning of the circular extrachromosomal form of SGI1.
Antibiotic susceptibility testing
The antibiotic susceptibility phenotype of P. mirabilis 18306 was determined by the disc diffusion method on Mueller–Hinton agar plates, according to the guidelines of the National Committee for Clinical Laboratory Standards.19 Many antibiotics were used, including ampicillin (10 µg), chloramphenicol (30 µg), streptomycin (10 µg), spectinomycin (100 µg), trimethoprim/sulfamethoxazole (25 µg), tetracycline (30 µg), ciprofloxacin (5 µg), gentamicin (10 µg), neomycin (30 µg), nalidixic acid (30 µg) and norfloxacin (10 µg). The discs were purchased from Nissui Pharmaceutical Co., Ltd (Tokyo, Japan) and the results were recorded on the basis of the zone size interpretative chart supplied by the manufacturer.
Bacterial DNA preparation, PCR and DNA sequencing of integrons
Overnight bacterial culture (200 µL) was mixed with 800 µL of distilled water and then boiled for 10 min. The resulting solution was centrifuged and the supernatant used as the DNA template. Amplification reactions were carried out with 10 µL of boiled bacterial suspensions, 250 µM deoxynucleoside triphosphate, 2.5 mM MgCl2, 50 pmol of primers, and 1 U of AmpliTaq Gold DNA Polymerase (Applied Biosystems, Roche, NJ, USA). Distilled water was added to bring the final volume to 50 µL. The primers 5'-CS and 3'-CS, which amplify the region between 5'-CS and 3'-CS of class 1 integrons (Table 1),20 were used for detection of class 1 integron, while class 2 integron was detected by using primers hep74 and hep51, which are specific to the conserved regions of class 2 integrons (Table 1).21 The PCR cycle included initial denaturation at 94°C for 10 min, followed by 30 cycles of denaturation for 1 min at 94°C, primer annealing for 1 min at 55°C, extension for 3 min at 72°C, and a final extension at 72°C for 10 min. The reaction products were subjected to electrophoresis in a 1.0% agarose gel, stained with ethidium bromide and visualized under UV light. The PCR fragment was then purified from the agarose gel using a QIAquick Gel Extraction Kit (Qiagen KK, Japan). Both DNA strands of the PCR product were sequenced using an ABI automatic DNA sequencer (Model 3730xl; Applied Biosystems).
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Amplification and mapping of the MDR region of SGI1 in P. mirabilis 18306
A complete map of the MDR region of SGI1 in P. mirabilis 18306 was made by establishing PCR linkage between most adjacent gene pairs, using the forward primer of the first with the reverse primer of the second, as well as longer linkages, as previously described (Table 1).6,10 Salmonella Typhimurium DT104 strain J-R2 carrying SGI1 was used as a positive control, and the PCR targets were confirmed by DNA sequencing.
Detection of the whole SGI1 in P. mirabilis 18306
To assess the presence of the entire SGI1, PCR assays were performed with sets of primers representing all regions of SGI1, as previously described (Table 1).11,22
Detection, cloning and sequencing of the circular extrachromosomal form of SGI1 of P. mirabilis 18306
Primers SGI1circ1 and SGI1circ2, oriented towards the left and right chromosomal SGI1 junctions, were used for detection of a circular extrachromosomal form of SGI1 in P. mirabilis 18306, as previously described (Table 1).16 These primers only amplify a product of 364 bp if SGI1 excises from the chromosome and circularizes by recombination between DR-L and DR-R of the integrated SGI1. The purified PCR fragment of the circular extrachromosomal form of P. mirabilis 18306 was cloned into the EcoRV-digested pBluescript II SK(–) (Stratagene, USA) using the TaKaRa Ligation Kit. Then, the ligation mixtures were used to transform E. coli TG1 competent cells. Bacteria were grown in LB agar medium supplemented with 50 mg/L of X-Gal, 1 mM IPTG and 100 mg/L of ampicillin. Positive colonies were screened by a white/blue selection protocol. The recombinant plasmid DNA was isolated from the transformed cells by using a QIAprep Spin Miniprep Kit (Qiagen KK, Japan), and the DNA sequence of the inserts was determined for both strands.
Computer analysis of the sequence data
A similarity search was carried out using the BLAST program, available at the NCBI BLAST homepage (http://www.ncbi.nlm.nih.gov/BLAST/).
Nucleotide sequence accession numbers
Nucleotide sequences of P. mirabilis 18306 SGI1-related dfrA15, blaP1 and attP attachment site were submitted to GenBank under accession numbers AB269788 [GenBank] , AB269789 [GenBank] and AB269790 [GenBank] , respectively, while Tn1826-derived class 2 integron was submitted to GenBank under accession number AB269891 [GenBank] .
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Multidrug resistance phenotype of P. mirabilis 18306 and its relation to SGI1 profile
P. mirabilis 18306 was isolated in March 2006 from a patient in Palestine with diabetic foot infection. This strain showed the typical multidrug resistance phenotype associated with SGI1, i.e. it was resistant to ampicillin, chloramphenicol, streptomycin, sulphonamides and tetracycline (ACSSuT), in addition to trimethoprim and nalidixic acid. The ACSSuT profile in Salmonella serovars was first noticed in Salmonella Typhimurium DT104 that was isolated from gulls and exotic birds in the early 1980s,7 and a few years later, this clone become epidemic in cattle and humans in the UK.8 In 1997, this phenotype, with additional resistance to trimethoprim and ciprofloxacin (ACSSuTTmCp resistance type), was noticed in epidemic strains of Salmonella Typhimurium DT104 in England and Wales,23 and then it was detected in various Salmonella serovars worldwide.7 The MDR phenotype of P. mirabilis 18306 is of great clinical significance because ampicillin, trimethoprim and tetracycline are among the antibiotics recommended for treatment of diabetic foot infection.24,25 Therefore, the selection of recommended antimicrobials for treatment of diabetic foot infection should be based on recent susceptibility tests for the isolated bacteria.
Detection and characterization of the antibiotic resistance gene cluster of SGI1 in P. mirabilis 18306
In an attempt to find a link between the MDR phenotype of P. mirabilis 18306 and SGI1, this isolate was tested for the presence of SGI1-related resistance genes. It is well known that all resistance genes of SGI1 are clustered in a region of 13 kb, called the MDR region.5 This region is basically a complex structure of the class 1 integron recently named In104.6 In104 contains a duplication of class 1 integron CSs, i.e. a pair of PCR products will be yielded by using the classic primers designed from the CSs of class 1 integrons.20 In the standard SGI1, these primers produce a characteristic pair of PCR products of 1.0 and 1.2 kb that contains two gene cassettes, aadA2 and blaP1, respectively. aadA2 confers resistance to streptomycin and spectinomycin, while blaP1 (also named blaPSE-1 or blaCARB-2) confers resistance to ß-lactam antibiotics. These gene cassettes flank the floR and tet(G) genes, which confer resistance to chloramphenicol–florfenicol and tetracyclines, respectively.
For characterization of the MDR region of SGI1 in P. mirabilis 18306, the strain was tested first for the presence of SGI1-associated class 1 integrons using Salmonella Typhimurium DT104 as a positive control. PCR results showed the expected pair of PCR products (1.0 and 1.2 kb) for Salmonella Typhimurium DT104, while for P. mirabilis 18306, one was 1.2 kb and the other was 0.75 kb in size (Figure 1). DNA sequencing results of the 1.2 kb product from P. mirabilis 18306 revealed that it was 1197 bp that showed complete identity to the blaP1 gene cassette previously identified in SGI1, while the other shorter product was 739 bp, and represents the dfrA15 gene cassette, which confers resistance to trimethoprim. This dfrA15 was identical to that recently detected in a large conjugative plasmid from Vibrio cholerae.26 dfrA15 was originally characterized in a plasmid from a commensal faecal E. coli in 1998.27 A similar SGI1 variant containing the dfrA15 gene cassette (named SGI1-L) has been recently reported in S. enterica serovar Newport.28 Of note, dfrA-related genes were previously identified in SGI1 variants from many Salmonella serovars, e.g. dfrA1 from Albany,14 Derby,6 Cerro,6 Emek6 and Dusseldorf,6 and dfrA10 from Agona,12,13 Kiambu6 and Infantis.6
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The other resistance genes of SGI1, floR, tet(G) and sul1, were detected in P. mirabilis 18306 by using pairs of primers internal to each gene, as previously described (Table 1).6 For these genes, P. mirabilis 18306 gave the same typical size of PCR products as that of the positive control Salmonella Typhimurium DT104 (data not shown). These results indicate that P. mirabilis 18306 typically contained the five antibiotic resistance genes of SGI1, with the exception that dfrA15 was detected instead of aadA2.
Complete mapping for the entire MDR region of SGI1 of P. mirabilis 18306
To confirm the location of these antibiotic resistance genes in SGI1 rather than in other locations, further mapping for the entire MDR region of SGI1 was carried out by establishing PCR and DNA sequencing linkage between most adjacent gene pairs, using the forward primer of the first with the reverse primer of the second, as well as longer linkages, as previously described. (Table 1 and Figure 2).6,10 By using PCR and DNA sequencing, we could identify a 10 200 bp fragment from P. mirabilis 18306 that showed homology to a 10 469 bp fragment in SGI1 of Salmonella Typhimurium DT104 (accession number AF261825 [GenBank] .2) (Figure 2).5 The gene cassettes array of this fragment in P. mirabilis 18306 was quite similar to that for Salmonella Typhimurium DT104, except that aadA2 in Salmonella Typhimurium DT104 was replaced with dfrA15 in P. mirabilis 18306 (Figure 2), while the other genes were typical. That was the reason for the 269 bp difference in size between the two fragments. The substitution of aadA2 with other gene cassettes has been reported previously in SGI1 variants. aadA2 has been replaced with two gene cassettes, aac(3)-Id and aadA7, in a variant SGI1 from Salmonella Newport.15 The aac(3)-Id and aadA7 were characterized for the first time in a class 1 integron from a multiresistant strain of Vibrio fluvialis by our group.29 Also aadA2 has been replaced by dfrA1 and a gene of unknown function, called orfC, in a variant SGI1 from Salmonella Albany.14
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Detection of the whole SGI1 in P. mirabilis 18306
To confirm the presence of the entire SGI1 in P. mirabilis 18306, PCR assays were performed with sets of primers representing all regions of SGI1, as previously described (Table 1 and Figure 2).11,22 The PCR results showed that P. mirabilis 18306 gave PCR amplicons for all primer sets, except for retron primers, with the same typical target sizes (Table 1) as the positive control, Salmonella Typhimurium DT104 (data not shown). These results indicate that P. mirabilis 18306 harbours the entire SGI1 without the retronphage region. Regarding the integration site of SGI1 into the chromosome, strikingly, P. mirabilis 18306 did not display any PCR products by using primers U7-L12 and LJ-R1 (left junction) and 104-RJ and 104-D primers (right junction) (Table 1 and Figure 2). These primers are usually used to confirm the integration of SGI1 into the S. enterica chromosome between the thdF and yidY genes.5,6,12 Thus, these results indicate that the integration site of SGI1 into the chromosome of P. mirabilis 18306 may be different from that of S. enterica. Of note, the existence of SGI1 in a plasmidic form was excluded as several different types of plasmid preparation procedures performed on P. mirabilis 18306 failed to reveal detectable plasmid DNA.
Characterization and analysis of circular extrachromosomal form of SGI1 of P. mirabilis 18306
Integration and excision of SGI1 into and from the host chromosome requires the formation of a circular but non-replicative extrachromosomal intermediate.16 This circular extrachromosomal intermediate is formed by recombination between short nearly identical sequences (18 bp), which are present in both the extrachromosomal form of SGI1 (attP) and at the 3' end of the thdF gene in the S. enterica chromosome (attB). Therefore, in all S. enterica serovars, SGI1 is flanked by imperfect 18 bp direct repeats at the left and right junctions in the chromosome. The presence of this circular extrachromosomal form is a strong indicator for the presence of the entire SGI1.16 Hence, a pair of primers, SGI1circ1 and SGI1circ2, which oriented towards the left and right chromosomal SGI1 junctions (Figure 2), were used for detection of a circular extrachromosomal form of SGI1, as previously described.16 Of note, these primers only amplify a product of 364 bp if SGI1 is excised from the chromosome and circularized by recombination between DR-L and DR-R of the integrated SGI1.16 After a two-step DNA amplification, a PCR fragment of the expected size (364 bp) was obtained from both Salmonella Typhimurium DT104 (positive control) and P. mirabilis 18306 (Figure 3). Then, the PCR product of P. mirabilis 18306, which represents the attP site of SGI1, was cloned, and both DNA strands of the insert were sequenced. The nucleotide sequence was compared with that of Salmonella Typhimurium DT104. Interestingly, nucleotide sequencing showed that the attP site of P. mirabilis 18306 was identical to that of Salmonella Typhimurium DT104 (data not shown), including the 18 bp direct repeats that are known to flank the SGI1 region. Therefore, this result confirms the above mentioned data related to the presence of the whole SGI1 in P. mirabilis 18306.
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Instability of SGI1 in P. mirabilis 18306
During our handling of P. mirabilis 18306 in the laboratory, we noticed that, in the absence of antibiotic selection, i.e. without adding antibiotic to the culture media, SGI1 was not stable in the P. mirabilis 18306, as most of its components could not be detected by PCR. However, this feature returned after the addition of antibiotics to the media (data not shown). This is contrary to the stability of SGI1 in our positive control, Salmonella Typhimurium DT104, in the absence of antibiotic selection. The stability of SGI1 in the chromosome of Salmonella Typhimurium DT104 in the absence of antibiotic selective pressure has been noticed previously.30 However, in another report, occasional inconsistency in the SGI1 integrons has been found in multiresistant Salmonella Typhimurium DT104 where integrons were lost and redetected again after two or more antibiotics were added in the enrichment phase.31 As we mentioned above, we could not detect any type of plasmids in P. mirabilis 18306, indicating that SGI1 does not present in a plasmidic form and the instability of SGI1 in this strain may be due to other mechanisms of mobility.
Characterization of Tn1826-derived class 2 integron in P. mirabilis 18306
Class 2 integron has an organization similar to that of class 1, but it is mostly associated with transposon Tn7, and it is known to carry three classic gene cassettes, dfrA1, sat (named as sat2) and aadA1, which confer resistance to trimethoprim, streptothricin and streptomycin/spectinomycin, respectively.32 However, class 2 integrons with a variation in composition of the cassette array have also been identified in other related transposons such as Tn1825 and Tn1826.33 In Tn1826, the class 2 integron is structurally similar to that of Tn7 but carries only two gene cassettes, sat2 and aadA1, i.e. dfrA1 is deleted.32,33 In this study, P. mirabilis 18306 was tested for the presence of class 2 integrons in an attempt to determine the mechanism of streptomycin resistance in this strain. PCR and DNA sequencing results characterized the class 2 integron with a fragment size of 1581 bp (data not shown). This class 2 integron is identical to that of Tn1826, and contains sat2 and aadA1 gene cassettes. This aadA1 gene may be responsible for streptomycin resistance in P. mirabilis 18306.
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In this study, we identified a new variant of the SGI1 antibiotic resistance gene cluster in a multidrug-resistant strain of P. mirabilis. In this variant dfrA15 replaced aadA2, while the other antibiotic resistance genes of standard SGI1 remained unchanged. We also characterized the circular extrachromosomal form of SGI1 and its attP attachment site in P. mirabilis. The presence of SGI1 with its MDR region in P. mirabilis, is the first report for this island outside genus Salmonella, and raises the alarming possibility of dissemination of this island to other more dangerous bacteria. Further studies are now underway to elucidate the molecular nature of this variant and the mechanism of its integration and instability in P. mirabilis.
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None to declare.
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A. M. A. is supported by a postdoctoral fellowship from the Japan Society for the Promotion of Science. This work was supported by a Grant-in-Aid for Scientific Research to T. S. from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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