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. 2015 Dec 31;60(1):703–708. doi: 10.1128/AAC.02192-15

Genome Analysis of Kingella kingae Strain KWG1 Reveals How a β-Lactamase Gene Inserted in the Chromosome of This Species

Philippe Bidet a,b,c, Romain Basmaci a,b,c, Julien Guglielmini a,b, Catherine Doit a,b,c, Christelle Jost a,b,c, André Birgy a,b, Stéphane Bonacorsi a,b,c,✉
PMCID: PMC4704243  PMID: 26574009

Abstract

We describe the genome of a penicillinase-producing Kingella kingae strain (KWG1), the first to be isolated in continental Europe, whose blaTEM-1 gene was, for the first time in this species, found to be chromosomally inserted. The blaTEM gene is located in an integrative and conjugative element (ICE) inserted in Met-tRNA and comprising genes that encode resistance to sulfonamides, streptomycin, and tetracycline. This ICE is homologous to resistance-conferring plasmids of K. kingae and other Gram-negative bacteria.

TEXT

Kingella kingae is recognized as the first pathogen causing osteoarticular infections in children younger than 4 years of age (1–4). To date, penicillinase-producing strains harboring the blaTEM-1 gene on a plasmid have been isolated only in the United States, Iceland, and Israel (5). Recently, we described the first penicillinase-producing K. kingae strain to be found in continental Europe, KWG1, isolated from a child with arthritis (6). Using a Southern blot hybridization approach, we showed that the blaTEM-1 gene was chromosomally inserted in KWG1, in contrast to all of the penicillinase-producing strains previously described so far in the literature. Here, we report the complete genome sequence of KWG1.

Sequencing was performed by the Pacific Biosciences SMRT method using P4C2 chemistry. A total of 55,284 reads with a quality of ≥0.8 and a mean length of 4,456 bp were obtained, and a de novo assembly was performed by using the HGAP3 pipeline available through SMRT Analysis (version 2.2) from Pacific Biosciences. The mean depth of coverage was 91×. Polished assembly allowed us to obtain a single unique contig. Annotation was performed by Progenus.

Insertion sequence (IS) annotation was performed with ISfinder (http://www-is.biotoul.fr), and the new IS, ISKki1, was deposited in its database (7). Conjugative system annotation was performed with CONJscan (http://mobyle.pasteur.fr/cgi-bin/portal.py#forms::CONJscan-T4SSscan) (8). Comparisons with other Kingella genomes and with antimicrobial resistance-associated plasmids were performed with the NCBI BLAST software (http://www.ncbi.nlm.nih.gov) and the Synteny Line Plot tool of the MaGe Platform (http://www.genoscope.cns.fr/agc/mage) (9).

The complete and circularized KWG1 genome is 2,140,065 bp long with a GC content of 46.48%. It contains 54 tRNAs, 4 rRNA operons, and 2,250 open reading frames (ORFs) coding for known or putative proteins.

Comparison with the K. kingae type strain ATCC 23330 genome (accession number AFHS00000000) shows that both strains have 1,842 orthologous ORFs in syntons (81.69%) and reveals that the blaTEM gene encoding the K. kingae KWG1 β-lactamase is located on a large (74-kb) genomic island (ORFs 904 to 973) absent from the type strain and inserted in the vicinity of Met-tRNA. A putative phage integrase (ORF 2251) is present at its 3′ end (Fig. 1; Table 1). A second putative phage integrase is found in a 3-kb region (ORFs 967 to 973) located at the 5′ end. This region is composed of phage-like genes surrounded by two inverted copies of the same IS (ISKki1) (Fig. 1; Table 1). The island has a global GC content of 49% and is composed of genes encoding resistance to various antimicrobial compounds, transposase genes, genes of phage origin, and genes associated with plasmid functions (transfer or replication). Among those encoding plasmid functions, CONJscan (8) identified 11 contiguous ORFs (955 to 965) as an MPFT (mating pair formation proteins similar to the archetypal T-DNA conjugation system of Agrobacterium tumefaciens plasmid Ti) type IV secretion system involved in conjugative transfer (10); it also detected a coupling protein (TraG, ORF 946) and a relaxase (ORF 944). All of these colocalizing elements define a full conjugative system, and consequently, the genomic island can be considered an integrative and conjugative element (ICE) (11).

FIG 1.

FIG 1

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Schematic representation of the putative genetic events that led to chromosomal insertion of the blaTEM gene in the K. kingae KWG1 genome and the genetic organization of the genomic region spanning bases 846108 to 926548. ORFs are represented by block arrows oriented according to the reading frame and color coded according to their putative functions or BLAST homologies. Green, K. kingae core genome (based on synteny with the K. kingae type strain ATCC 23330 genome); red, antimicrobial resistance; dark blue, plasmid transfer or replication; light salmon, RdgC-like protein in K. denitrificans strain ATCC 33394 (fragmented in KWG1); black, phage-like gene; light blue, IS or transposon (transposase, resolvase, and other); magenta, MPFT type IV secretion system; white, unknown function without homology or synteny with the K. kingae type strain genome. Transposons Tn10 and Tn5393c, as well as BLAST similarities to Salmonella enterica plasmid pSRC15, H. influenzae plasmid pA1606, K. kingae strain KK247, and K. denitrificans strain ATCC 33394, are indicated by colored horizontal double arrows. Syntenies with KWG1 are indicated by lines connecting ORFs with >50% identity on >80% of the shortest sequence. Isolated ISs (ISNme1 and ISKki1) are indicated by black horizontal arrows. Putative right and left att sites (attR and attL, respectively) and the 5-bp DR generated by insertion of the resistance region in the RgdC-like ORF are indicated by vertical red arrows. Tn5393c IRs (Tn5393 IR) and the 23-bp terminal IRs flanking Tn10 (Tn10 IR) are indicated by vertical green arrows.

TABLE 1.

Predicted ORFs, RNAs, and other genetic structures identified in the region of the K. kingae KWG1 genome spanning bases 846108 to 926548

Object Gene Product Frame Start End Length (bases) GC content Category
ORF-0902 dnaG DNA primase −2 846108 847871 1,764 0.4921 Core genome
ORF-0903 Conserved protein of unknown function −2 847971 849143 1,173 0.5107 Core genome
tRNA-15 Met-tRNA 1 849282 849357 76 RNA
RPT45590902 DR (putative AttL) 1 849311 849357 47 DR
ORF-2251 int Putative site-specific recombinase, phage integrase family −2 849303 850427 1,125 0.5060 Phage-like
ORF-0904 Conserved protein of unknown function −3 850916 851464 549 0.4699
ORF-0905 traL TraL protein −2 851451 852194 744 0.5013 Plasmid
ORF-0906 trbM TrbM −1 852373 852915 543 0.5378 Plasmid
ORF-0907 Conserved membrane protein of unknown function 3 853617 854255 639 0.4444
ORF-0908 Conserved protein of unknown function 1 854677 855135 459 0.4597
ORF-0909 Conserved protein of unknown function −3 855839 856228 390 0.4923
ORF-0910 DNA-binding helix-turn-helix protein −3 856895 857209 315 0.4984 Phage-like
ORF-0911 Conserved protein of unknown function −2 857193 857573 381 0.4777
ORF-0912 DNA-binding helix-turn-helix protein −2 857673 858275 603 0.4046 Phage-like
ORF-0913 Conserved protein of unknown function 1 858604 859422 819 0.5678
ORF-0914 Transposase, IS5 family, ISNme1 1 859948 860955 1,008 0.5179 Transposon
ORF-0915 Conserved exported protein of unknown function 1 861187 863475 2,289 0.5457
ORF-0916 Conserved protein of unknown function −3 863675 864952 1,278 0.4030
ORF-0917 Phage protein Gp37/Gp68 −1 864991 865734 744 0.4382 Phage-like
ORF-0918 Conserved protein of unknown function 1 867187 867918 732 0.5601
ORF-2252 Conserved protein of unknown function −2 868137 868511 375 0.4880
ORF-0919 mobC Bacterial mobilization protein MobC −3 869015 869545 531 0.4953 Plasmid
ORF-0920 Recombination-associated protein RdgC (fragment 1) −1 869617 869997 381 0.5696
5-bp DR flanking resistance region 1 870124 870128 5 DR
misc_feature870129D IR of Tn5393 1 870129 870208 80 Transposon
ORF-0921 strB Streptomycin phosphotransferase B −1 870235 871071 837 0.5591 Resistance
ORF-0922 strA Streptomycin 3″-kinase −2 871071 871874 804 0.5609 Resistance
ORF-0923 sul2 Dihydropteroate synthase type-2 −2 871935 872750 816 0.6078 Resistance
ORF-0924 repC RepC −2 873060 873869 810 0.6556 Plasmid
ORF-0925 blaTEM TEM-1 β-lactamase −1 873985 874845 861 0.4925 Resistance
ORF-0926 tnpR Tn3-like transposon resolvase, transposon Tn2a −2 875028 875585 558 0.5269 Transposon
ORF-0927 rep Replication protein −2 875919 876848 930 0.3527 Plasmid
ORF-0928 Integrase core genome domain protein 1 876898 877704 807 0.5279 Transposon
ORF-0929 pre Plasmid recombination enzyme −2 878208 879479 1,272 0.3852 Plasmid
ORF-2255 Putative transposase zinc-binding domain, fragment of ISCR2 +3 880263 880544 282 0.5890 Transposon
misc_feature880548D IR of Tn5393 1 880548 880627 80 Transposon
ORF-2253 strB Streptomycin phosphotransferase B −1 880654 881490 837 0.5591 Resistance
ORF-0930 strA Streptomycin 3″-kinase −2 881490 882293 804 0.5609 Resistance
9-bp repeat of Tn10 insertion 1 882338 882346 9 Transposon
misc_feature882340D Terminal IR of transposon Tn10 1 882340 882362 23 Transposon
misc_RNA_3 RNA-OUT −1 882385 882446 62 RNA
ORF-0931 Transposase, IS4 family, IS10 3 882447 883655 1,209 0.4475 Transposon
ORF-0932 tetD Transposon Tn10 TetD protein −2 883665 884081 417 0.3597 Resistance
ORF-0933 tetC Transposon Tn10 TetC protein 3 884094 884762 669 0.3259 Resistance
ORF-0934 tetA Class B tetracycline resistance protein −1 884875 886080 1,206 0.4328 Resistance
ORF-0935 tetR Class B tetracycline repressor protein from transposon Tn10 1 886162 886737 576 0.4097 Resistance
ORF-0936 jemC Conserved protein of unknown function −1 886762 887385 624 0.4119
ORF-0937 Conserved protein of unknown function −3 887456 887842 387 0.3902
ORF-0938 jemB Conserved protein of unknown function −2 887835 888134 300 0.3533
ORF-0939 jemA Glutamate transporter 2 888599 889804 1,206 0.3947
ORF-0940 Transposase, IS4 family, IS10 −1 890170 891378 1,209 0.4508 Transposon
misc_RNA_4 RNA-OUT 1 891379 891440 62 RNA
misc_feature891463R Terminal IR of transposon Tn10 −1 891463 891485 23 Transposon
9-bp repeat of Tn10 insertion −1 891479 891487 9 Transposon
ORF-0941 tnpR Putative resolvase for transposon Tn5393 −1 891514 892128 615 0.6065 Transposon
ORF-0942 tnpA Transposase TnpA for transposon Tn5393 3 892254 895139 2,886 0.6195 Transposon
misc_feature895093R IR of Tn5393 −1 895093 895172 80 Transposon
5-bp DR flanking resistance region 1 895173 895177 5 DR
ORF-0943 Recombination-associated protein RdgC (fragment 2) −2 895173 895565 393 0.5838
ORF-0944 traS TraS relaxase −3 895562 896680 1,119 0.5621 Plasmid
ORF-0945 Toprim domain protein −1 896779 902313 5,535 0.5429
ORF-0946 TraG/TraD family protein −3 902333 904372 2,040 0.5520 Plasmid
ORF-0947 ssb Single-stranded DNA-binding protein 1 −2 904467 904880 414 0.5845 Plasmid
ORF-2254 Putative metalloprotease +2 904925 905263 339 0.5580
ORF-0948 Conserved protein of unknown function −2 905223 905486 264 0.5568
ORF-0949 Conserved protein of unknown function −3 905618 905983 366 0.5519
ORF-0950 Conserved protein of unknown function −1 905980 906753 774 0.5581
ORF-0951 Conserved protein of unknown function −2 906798 907319 522 0.4540
ORF-0952 Conserved protein of unknown function −3 907316 908230 915 0.5607
ORF-0953 Conserved membrane protein of unknown function −1 907999 908325 327 0.5199
ORF-0954 Conserved exported protein of unknown function −1 908380 908844 465 0.4409
ORF-0955 virB11 P-type DNA transfer ATPase VirB11 −1 909004 910104 1,101 0.5595 MPFT
ORF-0956 virB10 Bacterial conjugation TrbI-like protein −3 910190 911464 1,275 0.5137 MPFT
ORF-0957 virB9 Putative P-type conjugative transfer protein VirB9 −1 911461 912300 840 0.5417 MPFT
ORF-0958 virB8 VirB8 protein −1 912313 913056 744 0.4449 MPFT
ORF-0959 virB7 Conserved protein of unknown function −2 913275 913754 480 0.4812 MPFT
ORF-0960 virB6 TrbL/VirB6 plasmid conjugal transfer protein −1 913786 914748 963 0.4798 MPFT
ORF-0961 virB5 Type IV secretion system protein −2 914808 915446 639 0.4507 MPFT
ORF-0962 virB4 Type IV secretion/conjugal transfer ATPase, VirB4 family −3 915548 918103 2,556 0.5082 MPFT
ORF-0963 virB3 Type IV secretory pathway, VirB3-like protein −2 918015 918443 429 0.4452 MPFT
ORF-0964 virB2 Conserved membrane protein of unknown function −3 918464 918784 321 0.5109 MPFT
ORF-0965 virB1 Type IV secretion system protein VirB1 −3 918941 919747 807 0.5502 MPFT
RPT45590902 DR (putative AttR) 1 919949 919995 47 DR
ORF-0966 Protein of unknown function −1 920122 920250 129 0.4496
ORF-0967 Transposase, ISKki1 ORF A 2 920342 920578 237 0.4093 Transposon
ORF-0968 Transposase, ISKki1 ORF B 2 920606 921172 567 0.3369 Transposon
ORF-0969 int Putative site-specific recombinase, phage integrase family −3 921179 922090 912 0.4748 Phage-like
ORF-0970 Conserved protein of unknown function −3 922112 922399 288 0.5104
ORF-0971 Replication protein A (fragment) −1 922408 922743 336 0.5060 Phage-like
ORF-0972 Transposase, ISKki1 ORF B −2 922761 923327 567 0.3351 Transposon
ORF-0973 Transposase, ISKki1 ORF A −2 923355 923591 237 0.4093 Transposon
ORF-0974 Conserved membrane protein of unknown function −2 923856 924728 873 0.5074 Core genome
ORF-0975 Conserved protein of unknown function 3 924783 925094 312 0.4679 Core genome
ORF-0976 fixS Cytochrome oxidase maturation protein, cbb3 type 1 925096 925272 177 0.4407 Core genome
ORF-0977 Major facilitator superfamily MFS_1 transporter 2 925229 926548 1,320 0.5136 Core genome
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ICEs are mobile genetic elements found in about 18% of prokaryotic chromosomes and display both plasmid and phage features (8, 11). Like plasmids, they harbor a conjugative system composed of a type IV secretion system (MPFT, ORFs 955 to 965), a coupling protein (ORF 946), and a relaxase (ORF 944). Like phages, they integrate into tRNA (tRNA-15) genes with integrases (ORF 2251). Evolutionary analyses suggest that ICEs derive from conjugative plasmids that acquired the phage-like ability to integrate into the chromosomes of bacteria (8). Of note, the KWG1 ICE harbors two putative plasmid replication genes (ORFs 924 and 927).

The presence of a 47-bp direct repeat (DR) sequence (RPT45590902; GAC TCA TAA TCC CTT GGT CGT GGG TTC GAA ACC CAC CCG ACC CAC CA) within the Met-tRNA gene and at the 5′ end of the MPFT cluster could represent an att site for the insertion of bacteriophages and/or ICEs (Table 1; Fig. 1). Resistance genes for streptomycin (strB and strA), sulfonamides (sul2), penicillin (blaTEM), and tetracycline (tetR, tetA, tetC, tetD) explaining the resistance profile of KWG1 are grouped together with genes encoding transposases and integrases in a small 25-kb region surrounded by two fragments of a truncated ORF encoding a putative exonuclease of the RdgC family (ORFs 920 and 943). Within this resistance region, streptomycin resistance-associated genes strA and strB are duplicated (ORFs 922 and 930 for strA, ORFs 921 and 2253 for strB). The resistance region is flanked by the inverted repeat (IR) of Tn5393 and a 5-bp (ATAAT) DR, suggesting direct insertion into the RdgC family ORF (Fig. 1).

The 74-kb-long ICE is 97% similar to a region of the Kingella denitrificans ATCC 33394 genome (GenBank accession number NZ_GL870929). This region contains the same conjugative system and thus also corresponds to an ICE but notably lacks two features, the 25-kb region encoding antimicrobial resistance and the 3-kb region at the 5′ end corresponding to ORFs 967 to 973 (Fig. 1). In K. denitrificans, this ICE is inserted in the vicinity of Asn-tRNA, with bases 68111 to 69268 of contig 15 (GenBank accession number AEWV01000015) probably encoding an undetected phage-like integrase that is close to a Kingella oralis putative phage integrase (GenBank accession number EEP68425; 80% identity on 86% coverage) but clearly different from KWG1 ORF 2251 (52% identity on 92% coverage). Interestingly, in K. denitrificans, the putative exonuclease of the RdgC family (ORF 850) corresponding to fragmented ORFs 920 and 943 of KWG1 is complete and undisrupted (Fig. 1); this confirms that the resistance region of KWG1 has been inserted into this putative exonuclease.

The resistance region appears as a complex structure combining elements of plasmids and transposons. Its 5′ part (ORFs 921 to 924) is nearly (99%) identical to the repC-sul2-strAB-rcr2Δ cluster of pSRC15 and other similar plasmids found in Gram-negative bacteria (12) (Fig. 1). The sul2-strAB-rcr2Δ cluster is supposed to result from the insertion of transposon Tn5393c into a CR2-sul2 region (12). Interestingly, a fragment of mobile element CR2 (rcr2Δ, ORF 2255) is found adjacent to the second copy of strAB (ORFs 2253 and 930) (Table 1; Fig. 1). Thus, the cluster of genes described by Yau et al. is present in two pieces separated by the central part carrying the blaTEM gene (Fig. 1) (12). The 3′ part of the resistance region (ORFs 2255 to 942) results from the insertion of transposon Tn10 (flanked by the 9-bp repeat CCCTGATGA and 23-bp 5′ terminal IRs) (13) into a Tn5393-like transposon (Tn5393c) (Fig. 1) (14). Finally, the central part carrying the blaTEM gene from ORF 925 to ORF 929 is substantially similar (98% over 82% coverage) to a small blaTEM-1-bearing plasmid in Haemophilus influenzae (pA1606; GenBank accession number JQ611726), as well as similar in organization (rep, replication gene; blaTEM-1, TEM-1 β-lactamase gene; pre, plasmid recombination enzyme gene; tnpR, Tn3-like transposon resolvase gene) (Fig. 1) (15). However, unlike pA1606, the tnpR resolvase gene of KWG1 (ORF 926) and its res sites (I, II, and III) display the closest similarity to those of transposon Tn2a (16); moreover, the blaTEM-1 gene (ORF 925) is the TEM-1c variant (17), while pA1606 harbors the TEM-1b variant.

Fourteen contigs of the blaTEM-harboring KKC2005004457 plasmid sequencing project (GenBank accession number AMPT00000000), with lengths ranging from 37 to 1,684 bases, are highly (99 to 100%) similar to the whole resistance region (18). However, because of the heavily fragmented nature of these contigs, we cannot tell if the architecture of this K. kingae resistance plasmid is similar to that of the KWG1 resistance region.

Two contigs of the β-lactamase-producing K. kingae KK247 strain sequencing project (GenBank accession number CCJT00000000) (19) are similar to parts of the ICE: contig 33 with the resistance region (98%) and contig 22 with the MPFT cluster and the 3′ end of the resistance region (99%) (Fig. 1).

The strong similarity observed between the ICE and contigs of K. kingae strains carrying resistance plasmids suggests that transitions between the episomal and plasmidic forms of blaTEM-encoding mobile genetic elements in this species do exist. This observation is in line with recent work that blurs the distinction between ICEs and plasmids (20).

Although no circularized complete sequence of a K. kingae resistance plasmid harboring the blaTEM gene is available to date, we may hypothesize the history of the insertion process with a reasonable degree of confidence (Fig. 1).

First, a small blaTEM-harboring plasmid, similar (but not identical) to pA1606, inserted in a larger region associated with resistance to tetracycline, sulfonamides, and streptomycin, near strAB, with duplication of these genes. Second, the whole resistance region is later inserted in a larger MPFT conjugative plasmid, causing disruption of a rdgC-like gene. Finally, the conjugative plasmid, or a part of it, inserted itself into the chromosome at Met-tRNA via a phage-like integration process. The precise order of these three events is only postulated and may have differed.

The fact that a similar plasmid is also inserted into the chromosome of K. denitrificans suggests that it is an integrative element of the Kingella genus. However, this plasmid inserted into another tRNA (Asn-tRNA) with a different integrase lacks several insertion sequences (ISNme1 and ISKki1) and does not carry any resistance gene. Recombination and transposition events have thus modified the architecture of this mobile genetic element during its transfer from one species to another.

Interestingly, KK247, described as a strain with plasmid-borne blaTEM, displays significant sequence similarity and a similar architecture for two of its contigs, suggesting that the ICE still exists in its plasmid form in K. kingae (19).

As KK247 belongs to clone A, a clone composed mainly of oropharyngeal commensal isolates different from the one to which KWG1 belongs, and as we have previously shown that some K. kingae strains belonging to clone A also carry an integrated blaTEM gene on their chromosome, we can conclude that the integration process of the resistance plasmid occurred at least twice in different phylogenetic groups (21).

Episomal integration confers on bacteria the advantage that resistance to antimicrobials is automatically transmitted to daughter cells without the need for plasmid replication. In the era of massive antibiotic use, bacteria harboring stable mechanisms of resistance to various antimicrobials have a selective advantage in colonizing the oropharynxes of children frequently treated with antibiotics. Strains of K. kingae clone A have been associated with asymptomatic carriage in Israel and are rarely involved in invasive infections (22). Conversely, KWG1 belongs to a clone involved in osteoarticular infections. The fact that the same plasmid can insert itself into different genetic backgrounds of Kingella raises concerns that another, more virulent, clone may also integrate the resistance genes in the future.

Nucleotide sequence accession number.

The genome project described here was deposited in the European Nucleotide Archive under accession number LN869922.

ACKNOWLEDGMENTS

We acknowledge the Laboratory of Bioinformatics Analyses for Genomics and Metabolism and the National Infrastructure France Genomique for their technical support of the expert annotation and comparative genomic tools (MicroScope platform). We thank Harry Kemble for his proofreading.

This work was supported in part by the Booster Innovation Fund of the Département de la Recherche Clinique et du Développement, DIRC Ile-de-France, Assistance Publique—Hôpitaux de Paris. The funders had no role in the study design, data collection and analysis, publication decision, or preparation of the manuscript.

We declare no conflicts of interest.

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