Journal of Antimicrobial Chemotherapy

JAC Advance Access originally published online on March 21, 2006
Journal of Antimicrobial Chemotherapy 2006 57(6):1065-1069; doi:10.1093/jac/dkl094

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The presence of a conjugative Gram-positive Tn2009 in Gram-negative commensal bacteria

Kayode K. Ojo¹, Nevada L. Ruehlen¹, Natasha S. Close¹, Henrique Luis², Mario Bernardo², Jorge Leitao² and Marilyn C. Roberts^1,*

¹ Department of Pathobiology Box 357238 School of Public Health and Community Medicine, University of Washington Seattle, WA 98195 USA ² Dental Hygiene Program, Lisbon Dental School, Faculty of Medical Dentistry, University of Lisbon Lisbon, Portugal

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^*Corresponding author. Tel: +1-206-543-8001; Fax: +1-206-543-4873; E-mail: marilynr{at}u.washington.edu

Received 25 January 2006; returned 10 February 2006; revised 22 February 2006; accepted 1 March 2006

	Abstract

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Objectives: To determine whether mef(A)-msr(D) and tet(M) genes are linked in representative Gram-negative isolates and/or transferred together during conjugation. To molecularly characterize the Acinetobacter junii element and compare the structure and sequence with the non-conjugative Streptococcus pneumoniae Tn2009 element.

Methods: PCR assays, DNA–DNA hybridization and sequencing of PCR products were used. Nucleotide sequences were determined at the integration site of the mef(A) element into Tn916 and upstream and downstream flanking regions of the element.

Results: A total of 10 mef(A)-msr(D)- and tet(M)-positive isolates carried conjugative element(s). The A. junii Tn2009 element was indistinguishable from S. pneumoniae Tn2009. The region upstream of the A. junii Tn2009 contained an orf that was 89–91% identical to an S. pneumoniae spr1206 gene found upstream of the streptococcal Tn2009. In the A. junii, the spr1206 gene was separated by 67 bp from the end of the Tn2009, while 29 bp were found separating spr1206 from the streptococcal Tn2009. The 1201 bp downstream A. junii sequences included 913 unique sequences.

Conclusions: A total of 10 different Gram-negative genera were found to carry the tet(M) genes, including the first description in three genera (Citrobacter, Proteus and Stenotrophomonas). All isolates were able to transfer the genes into 1 recipient with macrolide selection. Over 3000 bp were sequenced on each side of the insertion mef junction region in the A. junii and were indistinguishable from the streptococcal Tn2009. The A. junii Tn2009 element was flanked by an S. pneumoniae gene upstream and a unique sequence downstream, suggesting that the A. junii Tn2009 could be part of a larger element.

Keywords: macrolide resistance , tet(M) , mef(A)-msr(D)

	Introduction

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Previously we examined the frequency of seven macrolide resistance genes in 176 commensal oral and urine Gram-negative isolates. The mef(A) gene, coding for a macrolide efflux protein, was found in 73 isolates (41%) representing 12 genera and was the most frequently carried macrolide resistance gene identified.¹ All mef(A)-positive isolates from nine genera were able to transfer the gene to a recipient Enterococcus faecalis and/or Escherichia coli.¹ These isolates also carried the msr(D) gene, recently shown to confer macrolide resistance independently, downstream of the mef(A) gene.²,³ The >80% identity at the amino acid sequence level between mef genes associated with Tn1207.1, MEGA and tet(O)-mef(A) elements and their downstream orfs has resulted in the same genes being given different names.²–¹⁰ To avoid confusion, this study will use the gene names for the Tn1207.1 element, as previously described.¹,³,⁵,¹⁰

After identification of the mef(A) genes in Gram-negative bacteria,¹ we characterized a subset of the isolates for the presence of tetracycline resistance ribosomal protection protein (tet) genes and determined that 77% of the isolates tested did have these tet genes with 85% carrying the tet(M) gene, which is the most widely distributed acquired tet gene in bacteria.¹,⁶ The tet(M) gene is usually found associated with the Tn916–Tn1545 family of conjugative transposons.⁶,⁷ As we were finishing the tetracycline experiments, the Del Grosso et al. paper⁸ was published describing a Tn916–Tn1545 family element, the non-conjugative Tn2009, isolated from a Streptococcus pneumoniae. This was a composite element containing mef(A)-msr(D) genes and four downstream orfs (orf6, or7, orf and orf8) inserted into a Tn916-like element within the Tn916 orf6 gene just upstream of the tet(M) gene.⁷–⁹ This represented the first description of the mef(A)-msr(D) genes linked to a tet(M) gene and an additional two orfs previously found in mef elements.⁶ However, this was not the first description of a tetracycline ribosomal resistance gene linked to the mef(A)-msr(D) genes since we had previously sequenced a 12 kb region of a tetracycline- and erythromycin-resistant Italian Streptococcus pyogenes and showed that the mef(A)-msr(D), orf6, or7 and orf8 genes were linked downstream of a tet(O) gene, which codes for a tetracycline ribosomal protection protein highly related to that of the tet(M) gene.¹⁰

The aim of this study was to determine whether 10 mef(A)-msr(D)- and tet(M)-positive Gram-negative isolates could transfer all three genes by conjugation and to molecularly characterize one of these elements to determine whether the three genes were on a single mobile unit and whether that element was related to the Tn916–Tn1545 family of transposons.

	Materials and methods

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Bacterial isolates

A total of 10 mef(A)-msr(D)- and tet(M)-positive Gram-negative commensal bacteria, Acinetobacter junii 329, Citrobacter sp. 16, E. coli 11, Enterobacter cloacae 240, Klebsiella sp. 9, Pantoeae agglomerans 323, Proteus sp. 21, Pseudomonas sp. 333, Ralstonia pickettii 330 and Stenotrophomonas maltophilia 282, from healthy children in Lisbon, Portugal, who were part of a study assessing the safety of low-level mercury exposure from dental amalgam restorations, were used in this study.¹,¹¹ These isolates were selected because they carried the three resistance genes, mef(A)-msr(D) and tet(M), and had previously been shown to transfer the mef(A) gene to recipients.¹,¹² Ten previously characterized transconjugants which used the recipients E. faecalis JH2-2, E. coli HB101, Neisseria mucosa CTM1.1 and Neisseria perflava/sicca 86.000348, and selected for macrolide resistance, were included in the study.¹,¹¹,¹² One transconjugant from seven of the donors mated with the E. faecalis recipient, one transconjugant from A. junii mated with the N. mucosa and N. perflava/sicca recipients and the E. coli donor which mated with the E. coli recipient were included in the study.¹,¹¹,¹² The S. pyogenes 7008 carrying the mef(A) and tet(O) genes,¹⁰ Neisseria gonorrhoeae 7500 carrying the mef(A) gene¹³ and E. coli HB101 with no antibiotic resistance genes were used as controls for the various PCR assays. The A. junii was chosen because it did not carry rRNA methylase genes and could transfer the genes to all four of the recipients listed above. In addition, our previous study suggested that it might carry orfs1–8 ¹² as found in Tn1207.1; however, more recent work indicated that the probes used in that study were not specific enough to determine whether the complete orf1, orf2 and orf3 or just the short regions more recently identified in the tet(O)-mef(A) element were present.¹⁰

DNA–DNA hybridization

GeneScreen Plus membrane (NEN Research, Boston, MA, USA) and/or Graph Transfer Membrane (GE Nylon, Minnetonka, MN, USA) were used for the DNA–DNA hybridization of Southern blots, DNA dot blots and/or PCR dot blots made from the bacterial isolates, as described previously.¹,¹⁰–¹⁶ The blots were hybridized using ³²P-labelled probes to verify the PCR products as described previously.¹,¹⁰–¹⁶ The Tn916 orfs not sequenced were confirmed using ³²P-labelled specific oligonucleotide probes for each orf in DNA–DNA hybridization experiments.

PCR

The presence of the tet(M) gene in the transconjugants was determined as described previously using DNA–DNA hybridization and PCR assays with the PCR products hybridized with specific tet(M) primers.¹⁵,¹⁶ The screening PCR for the Tn2009-like element used primers for Tn916 orf6 and mef(A) to allow for identification of the recombination junction between Tn916 and the mef(A) containing element using an initial denaturation at 96°C for 3 min, 35 cycles of 96°C for 30 s, annealing at 50°C for 1 min and extension at 72°C for 5 min, and a final extension step at 72°C for 10 min. All assays were then held at 4°C. Amplification of the region upstream of Tn916 int and downstream of Tn916 orf23 was carried out using an arbitrary PCR assay with specific Tn916 primers, close to the end of the known sequence, and one of two primers from the mer operon, which were used as non-specific primers as previously described.¹¹,¹⁷ The PCR assay conditions were identical to those described above. When a second nested arbitrary PCR was run for the flanking regions of the composite transposon, the conditions were the same with the exception of the final extension, which was for 40 min rather than 10 min as described above. The amplicons were visualized on a 1.0% agarose gel. Confirmation of the PCR products was carried out by DNA–DNA hybridization using specific internal ³²P-labelled probes and/or by sequencing of the PCR product. All primers used are listed in Table 1.

View this table: [in this window] [in a new window]   Table 1. Oligonucleotide primers

 
Sequencing

The PCR amplicons were cloned into the pCR^®T7/NT-TOPO^® vector (Invitrogen, CA, USA) according to the manufacturer's instructions and sequenced using the T7 promoter forward and reverse primers. All of the nucleotide sequences were analysed using the Internet-based software from NCBI (http://www.ncbi.nlm.nih.gov/) and then assembled. The sequences of the insertion areas have been deposited under accession numbers as follows: DQ223649 [GenBank] , which covers sequences of the left flanking region into the Tn916 int gene (a); DQ223647 [GenBank] , which covers the left junction region and sequences from Tn916 orf10 to the end of the mef(A) gene (b); DQ223648 [GenBank] , which includes the right junction region and sequences from meforf7 into the tet(M) gene (c); and DQ223650 [GenBank] , which covers the downstream flanking region (d) (Figure 1). Primers used are listed in Table 1.

View larger version (20K): [in this window] [in a new window]   Figure 1. Diagram of the A. junii Tn2009 element. The regions sequenced are designated by diagonally striped boxes. The sequences of the four regions are listed as a, b, c and d, with GenBank accession numbers of DQ223649, DQ223647, DQ223648 and DQ223650, respectively. The sequences around the insertion of the mef(A)-orf8 genes are provided, as are the upstream and downstream junction sequences of the Tn2009 element with surrounding sequences. DQ223649 includes 1320 bp of the upstream flanking region (labelled a), DQ223647 covers 3270 bp of the left junction region and sequences from Tn916 orf10 to the end of the mef gene (labelled b), DQ223648 includes 3332 bp from the right junction region and sequences from MEGA orf7 into the tet(M) gene (labelled c), and DQ223650 includes 1201 bp of the downstream flanking region (labelled d). *These genes have been given different designations by different authors depending on the operon in question. Tn1207.1 has eight genes (orfs1–8), while the Mega element has five genes (orf1–5) which are genetically closely related to Tn1207.1 orf4–8.2,4,5,8–10 The two orf* are listed as orf6 and orf7 in Tn2009 but are unrelated to Tn1207.1 orf6–7.

 

	Results

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Linkage and co-transfer of the tet(M) and mef(A) genes

The A. junii, Citrobacter sp., E. coli, E. cloacae, Klebsiella sp., P. agglomerans, Proteus sp., Pseudomonas sp., R. pickettii and S. maltophilia all produced PCR products of correct sizes that hybridized with internal probes when the PCR assay using a forward primer in the tet(M) gene and a reverse primer in the mef(A) gene was performed (data not shown). Therefore, it was of interest to examine whether 10 transconjugants,¹,¹⁰ selected for macrolide resistance and representing the four different recipients, also received the tet(M) gene during conjugation. Using the same PCR assay as above, the 10 transconjugants produced PCR products of correct sizes that hybridized with internal probes. In contrast, the control isolates did not produce PCR products in this assay (data not shown). Using DNA–DNA hybridization and additional PCR assays we identified that 10 transconjugants carried the msr(D), orf6, orf7 and orf8 genes always found downstream of the mef(A) gene.²,³,⁸ This suggested that the 10 isolates and their transconjugants might carry elements with the mef(A) gene linked to the tet(M) gene and could be related to the Tn2009 element previously described in S. pneumoniae.⁸ To verify this hypothesis, A. junii 329 was chosen for further study because it carried only the mef(A) gene and the tet(M) gene, while most of the other original isolates carried rRNA methylase (erm) genes that are often associated with conjugative elements and could be the reason why both the mef(A) and the tet(M) genes co-transferred.¹

Characterization of the A. junii Tn2009

PCR assays were used that cover the upstream and the downstream junctions labelled b and c, respectively, in Figure 1. The PCR products were sequenced and we identified a 4 bp deletion at the site of integration within the Tn916 orf6 gene, and the same deletion was identified in the S. pneumoniae Tn2009 (GenBank accession no. AF376746).⁸ Outside the 4 bp deletion the Tn916 orf6 to the mef(A) gene were indistinguishable from previously sequenced Tn916 sequences (GenBank accession no. NC_006372). We sequenced 3270 bp from the 5' end of Tn916 orf10 through to the end of the mef(A) gene (labelled b in Figure 1) (GenBank accession no. DQ223647), which included the new orf identified in Tn2009, and 3332 bp from the 5' end of the MEGA orf7gene into the tet(M) gene (labelled c in Figure 1) (GenBank accession no. DQ223648), which also included an additional orf between orf7 and orf8 in Tn2009. The 7602 bp sequenced were indistinguishable from the sequences from streptococcal Tn2009. The remaining orfs were verified using DNA–DNA hybridization and/or PCR assays to construct the A. junii Tn2009 element (Figure 1).

Flanking sequences outside the Tn2009 element

We sequenced 691 bp upstream of the A. junii Tn2009 (labelled a in Figure 1) (GenBank accession no. DQ223649). Immediately upstream of the A. junii Tn2009 was a 67 bp sequence that had homology with 19 of the 29 bp found upstream in S. pneumoniae Tn2009. These regions are compared in Figure 1. This was followed by an orf that shared 91% bp and 89% amino acid identity with the spr1206 gene, coding for a hypothetical streptococcal protein and found upstream of the streptococcal Tn2009 (GenBank accession no. AF376746).

Downstream of A. junii Tn2009, 1201 bp were sequenced (labelled d in Figure 1) (GenBank accession no. DQ223650). The first 288 bp were indistinguishable from the downstream sequences found in S. pneumoniae Tn2009, including the 61 bp exogenous sequences.⁸ However, adjacent to this region was a 913 bp region that had no sequence homology with the S. pneumoniae spr1199 identified downstream of S. pneumoniae Tn2009;⁸ nor did it share significant homology with any other GenBank sequences. The 913 bp region had a 31% G + C, while the Tn2009 element had a 38.2% G + C and the A. junii chromosome had a 42% G + C.¹⁷ No tandem repeats were found, but overlapping series of direct, complementary, symmetric and inverted repeats were detected using the Internet-based analysis tool (http://wwwmgs.bionet.nsc.ru/mgs/programs/OligoRep/InpForm.htm).

	Discussion

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This is the first description of a conjugative transposon linking the mef(A)-msr(D) and tet(M) genes on a mobile element in a Gram-negative bacteria, as well as the first description of the tet(M) gene in three other Gram-negative genera (Citrobacter, Proteus and Stenotrophomonas). The tet(M) gene has the widest host range of any of the tet genes. The mef(A)-msr(D) genes are also widely distributed and include genera which may carry the tet(M) gene and those that do not.³,⁶ The presence of these conjugative elements that are able to transfer to both Gram-positive and Gram-negative recipients suggests that the host range identified in this study most likely is an underestimation of the current and/or potential host range.

We sequenced >6600 bp of the junctions region and verified the presence of a conjugative Tn2009 in A. junii 326 indistinguishable from the sequences from the S. pneumoniae Tn2009 element (labelled b and c in Figure 1). Unlike our earlier report,¹⁸ based on DNA–DNA hybridization, the A. junii Tn2009, like the streptococcal Tn2009, did not carry the complete orf1, orf2 and orf3 genes found in Tn1207.1, as determined by the sequencing of this region (labelled b in Figure 1). Directly upstream of the A. junii Tn2009 element was a 67 bp region compared with the streptococcal 29 bp region, followed by the S. pneumoniae spr1206 gene upstream in both (labelled a in Figure 1). Downstream there was a common 288 bp region followed by a 913 bp region in the A. junii isolate that was unique, while the streptococcal element was linked to another chromosomal S. pneumoniae gene.⁸ The 913 bp region had a 31% G + C content and was likely to have been acquired along with the Tn2009 element, suggesting that this element may be inserted into larger transposons.

We demonstrated the transfer of Tn2009 from A. junii into unrelated genera, while the streptococcal Tn2009 was not movable.⁸ Both transposons carry the int and xis genes which should allow for excision and integration of the element, and further work will be needed to determine the differences in mobility.¹⁹–²² However, the present work illustrates that the Tn2009 element is now in a Gram-negative species and the presence of this element should be considered whenever the three genes, mef(A)-msr(D) and tet(M), are found in a single isolate.

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None to declare.

	Acknowledgements

 
This study was supported by grant U01 DE-1189 and contract N01 DE-72623 from the National Institute of Dental and Craniofacial Research of the National Institutes of Health.

	References

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This Article Abstract FREE Full Text (PDF) All Versions of this Article: 57/6/1065    most recent dkl094v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Search for citing articles in: ISI Web of Science (4) Request Permissions Disclaimer Google Scholar Articles by Ojo, K. K. Articles by Roberts, M. C. Search for Related Content PubMed PubMed Citation Articles by Ojo, K. K. Articles by Roberts, M. C. Social Bookmarking          What's this?

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