Journal of Antimicrobial Chemotherapy

JAC Advance Access originally published online on May 23, 2006
Journal of Antimicrobial Chemotherapy 2006 58(1):18-22; doi:10.1093/jac/dkl213

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Identification of the plasmid-borne quinolone resistance gene qnrS in Salmonella enterica serovar Infantis

Corinna Kehrenberg¹, Sonja Friederichs², Anno de Jong², Geovana Brenner Michael¹ and Stefan Schwarz^1,*

¹ Institut für Tierzucht, Bundesforschungsanstalt für Landwirtschaft (FAL) Höltystr. 10, 31535 Neustadt-Mariensee, Germany ² Bayer HealthCare AG, Animal Health Division 51368 Leverkusen, Germany

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^*Corresponding author. Tel: +49-5034-871-241; Fax: +49-5034-871-246; E-mail: stefan.schwarz{at}fal.de

Received 9 March 2006; returned 4 May 2006; revised 4 May 2006; accepted 4 May 2006

	Abstract

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Objectives: A Salmonella enterica serovar Infantis isolate of avian origin was investigated for the presence of the gene qnrS, its transferability and its association with other resistance genes.

Methods: The Salmonella Infantis isolate was investigated for its susceptibility to antimicrobial agents and its plasmid content. Hybridization experiments and PCR assays were performed to identify the resistance genes while transformation and conjugation studies were conducted to show their transferability. The quinolone resistance-determining regions of the genes gyrA, gyrB, parC and parE were sequenced. Moreover, extended sequence analysis was performed to gain insight into the structure and organization of the qnrS gene area.

Results: The Salmonella Infantis isolate exhibited the Asp⁸⁷Tyr⁸⁷ mutation in gyrA, but no resistance-mediating mutations in the other target genes. It carried a conjugative plasmid, pINF5, on which a qnrS gene was detected in close proximity to a Tn3-like, bla_TEM-1-carrying transposon. Homology to the qnrS-carrying plasmid pAH0376 of Shigella flexneri was limited to the Tn3-qnrS region. Sequence analysis of an 13.4 kb region of pINF5 identified truncated insertion sequences of types IS26 and IS2 as well as an internal segment of the CS12 fimbrial gene cluster of Escherichia coli up- and downstream of the qnrS gene.

Conclusions: This is to the best of our knowledge the first report of a qnrS gene in a Salmonella isolate. The analysis of the regions flanking the qnrS gene suggested that this region developed in multiple steps that included not only the integration of insertion sequences and a Tn3-like transposon, but also interplasmid recombination events.

Keywords: Tn3 , IS26 , ciprofloxacin , nalidixic acid , gyrase , topoisomerase

	Introduction

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Fluoroquinolones are potent antimicrobial agents for the treatment of a variety of infectious diseases worldwide. They are commonly used in both human and veterinary medicine, and their use has contributed to the selection of fluoroquinolone-resistant bacteria.¹ Resistance to fluoroquinolones emerges typically through alterations in the target enzymes, DNA gyrase and topoisomerase IV, although changes in drug entry or efflux pump systems have also been reported.¹–³ In addition, decreased susceptibility to fluoroquinolones can be mediated by plasmid-borne resistance genes, named qnr.²,³ The qnrA gene, first detected in a Klebsiella pneumoniae isolate, codes for a 218-amino-acid protein that belongs to the pentapeptide repeat family and protects the DNA gyrase and topoisomerase IV from the action of quinolone agents, including the fluoroquinolones.⁴,⁵ Later on, plasmid-borne or chromosomal QnrA homologues, such as QnrA2 from Klebsiella oxytoca and QnrA-like putative progenitor proteins from Shewanella algae, respectively, were identified and shown to differ by only a few amino acid substitutions from the aforementioned QnrA protein.⁶,⁷ Although the QnrA protein produces only decreased susceptibility to fluoroquinolones, its presence appears to facilitate the development of mutations in the chromosomal target genes in vitro.⁸,⁹ In the meantime, plasmids carrying qnrA genes have been reported to occur in many countries in Europe, America and Asia and they seem to be more broadly distributed among enterobacterial species than first assumed.⁷,⁹,¹⁰

Recently, another two members of the pentapeptide repeat family of proteins have been identified, QnrB with several variants and QnrS.⁷,¹¹ In contrast to QnrB, which has been detected in different members of the Enterobacteriaceae, the QnrS determinant was only found in a single Shigella flexneri isolate in Japan.¹¹ The gene qnrS was located on a 2642 bp HindIII fragment of the 47 kb plasmid pAH0376. It codes for a 218-amino-acid protein that shares only 59% amino acid identity with QnrA.¹¹ However, nucleotide sequence analysis of the up- and downstream regions identified a Tn3-like transposon containing a TEM-1 ß-lactamase gene adjacent to the qnrS gene. On plasmid pAH0376, the qnrS gene was neither part of a sul1-type integron structure nor part of a gene cassette.¹¹

In the present study, we analysed a Salmonella enterica subsp. enterica serovar Infantis isolate that exhibited resistance to nalidixic acid and ampicillin as well as reduced susceptibility to ciprofloxacin for the presence of qnr genes and their genetic environment.

	Materials and methods

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Bacterial strain and susceptibility testing

The S. enterica serovar Infantis isolate no. 5 was collected in 2004 from a carcass sample in the course of a surveillance study for non-typhoidal Salmonella isolates from chickens in four European countries.¹² In vitro susceptibility testing by agar dilution or broth dilution methods followed the guidelines given in the CLSI document M31-A2.¹³ For quality control purposes, Escherichia coli reference strain ATCC 25922 was used.

Plasmid analysis, transformation and conjugation experiments

Plasmid DNA from Salmonella Infantis isolate 5 was extracted and purified following a modification of the alkaline lysis procedure.¹⁴ The plasmid was transferred into E. coli CS1562 by the CaCl₂ method and transformants were selected by incubation on Luria–Bertani (LB) agar plates containing 30 mg/L ampicillin.¹⁵ Transformants were screened for their plasmid content and resistance phenotype. To investigate the transferability of plasmid pINF5, conjugation experiments using the rifampicin-resistant E. coli recipient strain HK225 were performed as described previously.¹⁴,¹⁵ Plasmids obtained from the transconjugants and transformants were purified and digested using the restriction enzymes KpnI, PvuII, PstI, HindIII, BglII and SspI for size estimation and pattern comparisons.

PCR amplification and sequencing

The quinolone resistance-determining regions (QRDRs) of gyrA, gyrB, parC and parE of Salmonella Infantis isolate 5 were amplified by PCR using genomic DNA. For the amplification of the QRDRs, slightly modified primers as described previously were used.¹⁶,¹⁷ To screen for the presence of qnrA, qnrB and qnrS genes, the following PCR primers were used: qnrA-fw: 5'-TCAGCAAGAGGATTTCTCA-3' and qnrA-rv: 5'-GGCAGCACTATGACTCCCA-3',⁹ qnrB-fw: 5'-TCGGCTGTCAGTTCTATGATCG-3' and qnrB-rv: 5'-TCCATGAGCAACGATGCCT-3' as well as qnrS-fw: 5'-TGATCTCACCTTCACCGCTTG-3' and qnrS-rv: 5'-GAATCAGTTCTTGCTGCCAGG-3'. The protocol for the qnr PCR included the use of Pwo-polymerase (Peqlab, Erlangen, Germany) under the following conditions: initial cycle of 94°C for 1 min, followed by 34 cycles of 1 min at 94°C, 2 min at an annealing temperature of 50°C (qnrA), 54°C (qnrB) or 58°C (qnrS) and 3 min at 72°C, with a final extension step of 7 min at 72°C. PCR detection of the bla_TEM gene followed a previously reported protocol.¹⁸ Sequencing of all PCR amplification products was performed as described previously.¹⁴

Hybridization experiments and DNA cloning

To identify the location of the qnrS gene, Southern-blot hybridization was performed using PstI- or HindIII-digested pINF5 DNA and the qnrS amplicon as a gene probe. For this, the DIG-High Prime DNA labelling and detection system (Roche, Diagnostics GmbH, Mannheim, Germany) was used and signal detection followed the recommendations given by the manufacturer. Subsequently, the qnrS-carrying PstI and HindIII fragments of pINF5 were cloned into the vector pBluescript II SK+ (Stratagene, Amsterdam, The Netherlands). Recombinant plasmids were transformed into competent E. coli JM109 cells.¹⁵ The nucleotide sequences of the cloned qnrS-carrying fragments were determined first; additional sequences of the flanking regions were then determined by primer walking (MWG, Ebersberg, Germany) starting from the sequences of the qnrS-carrying clones. For this, purified plasmid DNA of the E. coli CS1562::pINF5 transformant was used as template. Sequence analysis was performed with the BLAST programs blastn and blastp (http://www.ncbi.nlm.nih.gov/BLAST) and with the ORF Finder program (http://www.ncbi.nlm.nih.gov/gorf/gorf.html). The nucleotide sequence of the qnrS gene and its flanking regions has been deposited in the EMBL database under accession number AM234722.

	Results and discussion

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Identification of plasmid pINF5

MICs of ampicillin, nalidixic acid and ciprofloxacin for Salmonella Infantis isolate no. 5 were >128, >128 and 1 mg/L, respectively. PCR-directed analysis of the QRDRs revealed the Asp⁸⁷(GAC)Tyr⁸⁷ (UAC) mutation in gyrA whereas the QRDRs of gyrB, parC and parE did not exhibit the presence of resistance-mediating mutations. The Asp⁸⁷Tyr⁸⁷ mutation has previously been described in isolates of several other S. enterica subsp. enterica serovars.¹,²,¹⁶ Salmonella Infantis isolate no. 5 carried a single conjugative plasmid of 58 kb, designated pINF5, which mediated resistance to ampicillin and decreased susceptibility to fluoroquinolones. As compared with E. coli CS1562, the E. coli CS1562::pINF5 transformant revealed a 4-fold increase in the MIC of nalidixic acid to 2 mg/L, an at least 16-fold increase in the MIC of ciprofloxacin to 0.12 mg/L and a >512-fold increase in the MIC of ampicillin to >128 mg/L. PCR-directed detection of qnr genes revealed the presence of an amplicon of 566 bp indicative for qnrS. Restriction analysis with BglII as well as sequence analysis of this amplicon confirmed the presence of an internal segment of the qnrS gene. PCR analysis also identified a bla_TEM-type gene on plasmid pINF5. Hybridization studies confirmed the location of both resistance genes on plasmid pINF5. Restriction analysis of plasmid pINF5 with HindIII revealed a fragment pattern different from that previously described for the qnrS-carrying plasmid pAH0376 from S. flexneri.¹¹ Hybridization experiments with the qnrS amplicon as a probe identified this gene on an 3.6 kb PstI fragment and an 2.6 kb HindIII fragment. A pINF5 segment of 13 389 bp, which included these qnrS-carrying PstI and HindIII fragments, was sequenced and analysed for the qnrS gene and its flanking regions. A map of this segment from plasmid pINF5 in comparison with the corresponding region of plasmid pAH0376 is shown in Figure 1.

View larger version (22K): [in this window] [in a new window]   Figure 1. Comparison of the sequenced parts of plasmids pAH0376 from S. flexneri and pINF5 from Salmonella Infantis. A distance scale in kb is presented below each map. The reading frames are shown as arrows with the arrowhead indicating the direction of transcription. The arrows marked as 213, 259, 213 and 196 in the map of pINF5 indicate reading frames for hypothetical proteins of 213, 259, 213 and 196 amino acids, respectively. It should be noted that the two reading frames for the 213-amino-acid proteins differ distinctly in their deduced amino acid sequences. The 5 bp direct repeats at the boundaries of the Tn3 elements in pAH0376 and pINF5 as well as the 4 bp direct repeats at the outside boundaries of the truncated IS26 are shown in boxes. The black, stippled and striped boxes indicate the terminal inverted repeats of Tn3, IS26 and IS2, respectively. Grey-shaded areas indicate homologies to the sequences indicated below the map of pINF5. In addition, the area of homology between plasmids pAH0376 and pINF5 is also shown by grey shading.

 
Structure and organization of the qnrS gene area of plasmid pINF5

The initial 870 bp of the sequenced part of plasmid pINF5 revealed only two mismatches as compared with part of the E. coli plasmid pMUR050.¹⁹ A reading frame for a hypothetical protein of 213 amino acids was detected in this pMUR050-homologous part. Immediately thereafter, a 44 bp remnant of IS26 (positions 871–914) including the left terminal repeat was found.²⁰ It was followed by a Tn3-like transposon (positions 915–5864) that consisted of two perfect terminal inverted repeats of 38 bp and three reading frames for a TEM-1 ß-lactamase of 286 amino acids, a resolvase of 197 amino acids and a transposase of 849 amino acids. The entire Tn3 element revealed 97.1% nucleotide sequence identity to the original Tn3 from E. coli²¹ and 99.9% identity to the Tn3 element of plasmid pAH0376 from S. flexneri.¹¹ Downstream of the terminal inverted repeat of Tn3, a relic of an IS2-like insertion sequence was detected (positions 5865–6980). This IS2 relic consisted of an intact reading frame for a protein of 131 amino acids that showed 72.5% amino acid identity and 86.3% similarity to the 136-amino-acid transposase protein of IS2. Furthermore, a truncated reading frame of 543 bp for the IS2-associated resolvase protein was detected. The 42 bp terminal repeat detected in this IS2 relic corresponded in 30 of the 42 bp to the right terminal repeat of IS2.²²,²³ The qnrS gene was found at positions 7284–7940. The amino acid sequence deduced from the nucleotide sequence of qnrS of Salmonella was indistinguishable from that of QnrS from S. flexneri.¹¹ About 320 bp downstream of the qnrS gene, the 3' end of a reading frame (positions 8259–8696) whose deduced amino acid sequence showed 89.4% identity and 92.2% similarity to the C-terminal 144 amino acids of the TnpR resolvase protein of the broad host range mercury resistance plasmid pSB102 was detected.²⁴ This truncated reading frame was followed by a 61 bp that did not reveal homology to the sequences deposited in the databases. The adjacent 2689 bp segment showed 84.1% nucleotide sequence identity to part of the E. coli CS12 fimbrial gene cluster (database accession no. AY009096). Within this segment, three reading frames for hypothetical proteins of 259, 217 and 196 amino acids and a fourth reading frame for a 159-amino-acid protein, whose deduced amino acid sequence revealed 83.1% identity to a putative resolvase from E. coli, were detected. Interspersed by a 92 bp sequence that revealed no striking homology to other sequences in the databases, the pINF5 sequence continued with a 781 bp segment of IS26 (positions 11 539–12 319) including the reading frame for a 238-amino-acid transposase protein and the 14 bp right terminal repeat.²⁰ Adjacent to this IS26 relic, another stretch of pMUR050-homologous sequences (positions 12 320–13 389) including the reading frame for a 198-amino-acid resolvase protein (positions 12 612–13 208) was detected.¹⁹

Evolution of the qnrS gene region of plasmid pINF5

An overall comparison of the qnrS regions of plasmids pAH0376 from S. flexneri and pINF5 from Salmonella Infantis revealed that the Tn3-qnrS area was highly conserved in both plasmids whereas the upstream regions differed distinctly. Neither homology to pMUR050 nor an IS26 remnant were detectable upstream of Tn3 in pAH0376.¹¹ Since sequence analysis of plasmid pAH0376 ended in the resolvase reading frame downstream of qnrS, there is also no information about the presence of part of the fimbrial gene cluster and the adjacent downstream regions in pAH0376.

Based on the sequence features seen in the 13.4 kb part of plasmid pINF5, the qnrS gene area might have developed in different steps (Figure 2). It is assumed that initially an insertion sequence of type IS26 integrated into a pMUR050-like ancestor plasmid. Although IS26 has been reported to generate an 8 bp duplication of its target sequence,²⁰ we detected only the 4 bp direct repeat GTAA immediately upstream (positions 867–870) and downstream (positions 12 320–12 323) of the IS26 parts in the pINF5 sequence. As a next step, the integration of the Tn3-like transposon into the IS26 sequence is believed to have occurred. Tn3 is known to integrate preferentially into A+T-rich sequences and produce 5 bp direct repeats at its integration site.²⁵ In the present case, the 5 bp sequence TTATT, which is part of the IS26 sequence,²⁰ was found exactly at the boundaries of both IS26 relics (positions 910–914 and 11 539–11 543). Due to the lack of sequences for comparisons, it is not possible to determine in retrospect whether the entire remaining part including the qnrS gene has integrated into this IS26-Tn3 cointegrate in toto or whether the formation of this segment of pINF5 required multiple insertional and/or recombinational steps. The latter process is more likely since we detected truncated reading frames for resolvase proteins up- and downstream of the qnrS gene. The close proximity to an IS2 relic might indicate that insertion sequences play a role in the mobility of the qnrS gene. An interesting observation was the detection of the 5 bp sequence TAAAA at the junction of Tn3 and the qnrS gene region in pINF5. This sequence was originally found as a 5 bp direct repeat at the boundaries of Tn3 in plasmid pAH0376.¹¹ Its presence in pINF5 may point towards an interplasmid recombinational event of a pAH0376-like plasmid carrying a Tn3 and the qnrS gene area with a pMUR050-like ancestor plasmid carrying an IS26::Tn3 element. Recombination via Tn3 may result in the transfer of the qnrS gene area of pAH0376 into the pINF5 precursor plasmid. Since the sequence of pAH0376 deposited in the databases ends within the res reading frame downstream of qnrS, further speculation on the extent of sequences exchanged between a pAH0376-like plasmid and a pINF5 precursor is not possible. As a consequence, it is not possible to determine in retrospect the way by which part of the CS12 fimbrial gene cluster of E. coli became integrated into this region. However, the observation that the CS12 fimbrial gene cluster, which according to the database entry AY009096 is identical to the 987P fimbrial gene cluster, has been found on a plasmid²⁶ also suggests that interplasmid recombination events may have led to the incorporation of part of this cluster into plasmid pINF5.

View larger version (14K): [in this window] [in a new window]   Figure 2. Model for the evolution of the resistance gene region of plasmid pINF5 via IS26 and an IS26::Tn3 cointegrate. Grey shading indicates the areas of nucleotide sequence identity. The 4 and 5 bp direct repeats at the integration sites of IS26 and Tn3 are shown in boxes. For other features, see legend to Figure 1.

 
Finally, it should be noted that, although qnrS and the Tn3-associated ß-lactamase gene bla_TEM-1 are located in close proximity, both resistance genes are not physically linked. This is in contrast to the recently described physical linkage between the Tn3-associated bla_TEM-135 gene and the Tn1721-associated tet(A) tetracycline resistance gene on a plasmid from S. enterica serovar Typhimurium.¹⁸ The presence of the characteristic 5 bp direct repeats immediately up- and downstream of Tn3 in plasmid pAH0376 (TAAAA) and in plasmid pINF5 (TTATT) as described above strongly suggests that the integration of Tn3 in both plasmids from S. flexneri and Salmonella Infantis occurred independently from the acquisition of the qnrS gene.

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None to declare.

	Acknowledgements

 
We thank Vera Nöding for excellent technical assistance. This study was financially supported by Bayer HealthCare AG.

	References

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				J.-J. Wu, W.-C. Ko, S.-H. Tsai, and J.-J. Yan Prevalence of Plasmid-Mediated Quinolone Resistance Determinants QnrA, QnrB, and QnrS among Clinical Isolates of Enterobacter cloacae in a Taiwanese Hospital Antimicrob. Agents Chemother., April 1, 2007; 51(4): 1223 - 1227. [Abstract] [Full Text] [PDF]

				L. Poirel, V. Cattoir, A. Soares, C.-J. Soussy, and P. Nordmann Novel Ambler Class A {beta}-Lactamase LAP-1 and Its Association with the Plasmid-Mediated Quinolone Resistance Determinant QnrS1 Antimicrob. Agents Chemother., February 1, 2007; 51(2): 631 - 637. [Abstract] [Full Text] [PDF]

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