Nucleotide sequence analysis of NPS-1 β-lactamase and a novel integron (In1427)-carrying transposon in an MDR Pseudomonas aeruginosa keratitis strain

Nucleotide sequence analysis of NPS-1 β-lactamase and a novel integron (In1427)-carrying... Sir, The gene encoding NPS-1 β-lactamase (blaNPS-1) was first reported on a self-transmissible plasmid of clinical isolates of Pseudomonas aeruginosa.1 The enzyme can hydrolyse carbenicillin, azlocillin, cefoperazone and cefsulodin, but cannot effectively hydrolyse more stable β-lactams (cefotaxime, ceftazidime, ceftriaxone, monobactam and imipenem).1 Furthermore, blaNPS-1 was encoded on a mobile element of a large conjugative plasmid (pB4) isolated from an activated sludge,2 which shows that blaNPS-1 may rapidly transfer between different species from different sources. In the current study, we report an NPS-1-associated Tn3-like complex transposon in a microbial keratitis isolate of P. aeruginosa. An MDR P. aeruginosa strain (PA34) was isolated from a microbial keratitis patient in India (MIC in Table S1, available as Supplementary data at JAC Online). WGS was performed using MiSeq (Illumina, San Diego, CA, USA) generating 300 bp paired-end reads and a Nextera XT DNA library preparation kit (Illumina) was used to prepare the library. CLC Genomics Workbench 10.0 (QIAGEN Bioinformatics, Aarhus, Denmark) was used to assemble the raw reads. A total of 2 365 558 trimmed reads were assembled into 75 contigs >10 kb with an average coverage of 85×. The nucleotide sequence of the transposon is available under the GenBank® accession number MF487840. Itinerary BLASTn® has revealed that the draft genome of PA34 carries a class 1 integron that is located within a Tn3-like transposon.3 The integron has a locus containing two gene cassettes comprising genes for trimethoprim (dfrA15) and chloramphenicol (cmlA1) resistance. Analysis of the nucleotide sequence flanking these two cassettes revealed important characteristics of gene cassettes which included attC sequences downstream of the dfrA15 and cmlA1 genes. See Figure 1(a and b). The dfrA15 of PA34 is identical to that of many enteric bacteria,4 suggesting this may be their source of origin. Furthermore, the cmlA1 gene was similar to a chromosomal chloramphenicol efflux transporter (U12338.3). This indicates that acquisition of a chromosomal gene may have occurred in the integron as a gene cassette. As trimethoprim and chloramphenicol are not a choice in treatment regimens for P. aeruginosa infections owing to its natural resistance, the presence of dfrA15 and cmlA1 gene cassettes may be of less concern. However, their presence in isolates from the eye, which is a site of interaction of a heterogeneous microbial community, may indicate the potential source of transferable resistance traits. This integron has a new array of gene cassettes and was named In1427, a novel class I integron.5 A characteristic orf5 of the integron was truncated by IS6100, which has also been reported to disrupt an integron in Klebsiella oxytoca.6 This suggests that IS6100 may be responsible for introduction of In1427 into the transposon of PA34. Figure 1 View largeDownload slide Schematic representation of the features of the Tn3 transposon of PA34. The genes of each segment are shown by arrows, indicating assigned functions and the direction of transcription: grey with black border indicates resistance genes and white with black border indicates genes responsible for transposition. (a) Map of the major features of the complete transposon. Mobile elements are indicated by the lines below the sequence. The black solid triangles at the end of lines indicate a repeat region of the elements. A single triangle appearing on the mobile element line means it is truncated. The dotted line indicates the position of the class 1 integron. The schematic is drawn to scale by Easyfig9 with minor modification. (b) Details of the arrangement of the resistance gene cassette in the integron (In1427). PintI1, promoter for transcription of gene cassettes; intI1, integrase gene; attI1, integration site; dfrA15, type I dihydrofolate reductase; cmlA1, chloramphenicol transporter; attC, cassette boundary (59-base element); qacEΔ1, partially deleted gene that encodes quaternary ammonium compound resistance; sul1, sulphonamide resistance; △orf5, truncated gene of unknown function. Numbers correspond to number of bp (map not drawn to scale). (c) A genetic map of Tn5393c of Aeromonas salmonicida subsp. salmonicida (AF262622.1) (5670 bp) and the homologous structure in Tn3-like transposon of PA34. The segment in the rectangular box represents genes inserted in the original structure of Tn5393c and the downward arrow indicates the location of homologous genes. (d) The genetic environment of the blaNPS-1 gene region from plasmid pB4. Numbers correspond to number of bp. Figure 1 View largeDownload slide Schematic representation of the features of the Tn3 transposon of PA34. The genes of each segment are shown by arrows, indicating assigned functions and the direction of transcription: grey with black border indicates resistance genes and white with black border indicates genes responsible for transposition. (a) Map of the major features of the complete transposon. Mobile elements are indicated by the lines below the sequence. The black solid triangles at the end of lines indicate a repeat region of the elements. A single triangle appearing on the mobile element line means it is truncated. The dotted line indicates the position of the class 1 integron. The schematic is drawn to scale by Easyfig9 with minor modification. (b) Details of the arrangement of the resistance gene cassette in the integron (In1427). PintI1, promoter for transcription of gene cassettes; intI1, integrase gene; attI1, integration site; dfrA15, type I dihydrofolate reductase; cmlA1, chloramphenicol transporter; attC, cassette boundary (59-base element); qacEΔ1, partially deleted gene that encodes quaternary ammonium compound resistance; sul1, sulphonamide resistance; △orf5, truncated gene of unknown function. Numbers correspond to number of bp (map not drawn to scale). (c) A genetic map of Tn5393c of Aeromonas salmonicida subsp. salmonicida (AF262622.1) (5670 bp) and the homologous structure in Tn3-like transposon of PA34. The segment in the rectangular box represents genes inserted in the original structure of Tn5393c and the downward arrow indicates the location of homologous genes. (d) The genetic environment of the blaNPS-1 gene region from plasmid pB4. Numbers correspond to number of bp. The transposon also possesses three other antibiotic resistance genes: two aminoglycoside-modifying enzymes (AMEs) and one β-lactamase (NPS-1) (Figure 1a). The first AME is APH(3’’)-Ib, identical to strA from Pseudomonas sp. B13, and the second AME is APH(6)-Id, identical to strB from Mycobacterium abscessus subsp. bolletii F1725 plasmid BRA100. Tauch et al.2 have described that the strA–strB gene pair in Tn5393c was highly transferable among bacteria isolated from plants, animals and humans. However, the original structure of Tn5393c, which was found first in the R plasmid pRAS2 from the fish pathogen Aeromonas salmonicida subsp. salmonicida (AF262622.1),7 was interrupted in PA34 by a 5735 bp region that also included another resistance gene (blaNPS-1). The segment was inserted between the tnpR and strA–strB pairs (Figure 1c). An ISPsy42 (Tn3 family) was found in the region between 9711 and 15 439 bp of the transposon. This suggests that Tn5393c may have the capacity to be integrated by other mobile elements that may be incorporated into resistance genes (blaNPS-1 in this case). A putative mobile element (Tn6205) was found between two resolvase genes and was associated with the strA, strB and blaNPS-1 genes (Figure 1a). The Tn6205 also disrupted the second tnpA. This genetic organization of a Tn3-like transposon of PA34 suggests that insertion and recombination of antibiotic resistance genes may have occurred in multiple steps and dissemination of antibiotic resistance may have occurred between distantly related bacteria. blaNPS-1 was inserted between tnpR and strA and its genetic environment is different in PA34 than that previously reported in the plasmid pB42 (Figure 1d). In PA34, blaNPS-1 is associated with Tn3-like transposons along with aminoglycoside resistance genes. This suggests that blaNPS-1 can be found in different genetic environments and may have different sources in the environment. The nucleotide sequence of blaNPS-1 was 100% similar to plasmid pMLH50 (from a clinical isolate),8 but only 99.74% similar to plasmid pB4 (from environmental isolates)2 and a draft genome sequence of Pseudomonas stutzeri 40D2 (MWUI01000033.1) (M. S. R. Shuvo, S. Bashar, M. Karmaker, N. Chauhan, P. Nilawe, M. Sultana and M. A. Hossain, unpublished data). This suggests that blaNPS-1 is circulating in environmental resistance gene pools and can be acquired and maintained in clinical isolates. Further research will help ascertain the exact location of the transposon in the PA34 genome. In conclusion, the current study shows that an ocular isolate of P. aeruginosa may act as a reservoir of resistance genes. Acknowledgements We would like to acknowledge the Singapore Centre for Environmental Life Sciences Engineering (SCELSE), whose research is supported by the National Research Foundation Singapore, Ministry of Education, Nanyang Technological University and National University of Singapore, under its Research Centre of Excellence Programme. Sequencing of DNA was carried out with the help of Daniela Moses and Stephan Schuster using the sequencing facilities at SCELSE. Funding Funding was provided by the School of Optometry and Vision Science, University of New South Wales. Transparency declarations None to declare. Supplementary data Table S1 is available as Supplementary data at JAC Online. References 1 Livermore DM , Jones CS. Characterization of NPS-1, a novel plasmid-mediated β-lactamase, from two Pseudomonas aeruginosa isolates . Antimicrob Agents Chemother 1986 ; 29 : 99 – 103 . Google Scholar CrossRef Search ADS PubMed 2 Tauch A , Schluter A , Bischoff N et al. The 79,370-bp conjugative plasmid pB4 consists of an IncP-1β backbone loaded with a chromate resistance transposon, the strA-strB streptomycin resistance gene pair, the oxacillinase gene blaNPS-1, and a tripartite antibiotic efflux system of the resistance-nodulation-division family . Mol Genet Genomics 2003 ; 268 : 570 – 84 . Google Scholar PubMed 3 Kung VL , Ozer EA , Hauser AR. The accessory genome of Pseudomonas aeruginosa . Microbiol Mol Biol Rev 2010 ; 74 : 621 – 41 . Google Scholar CrossRef Search ADS PubMed 4 Adrian PV , du Plessis M , Klugman KP et al. New trimethoprim-resistant dihydrofolate reductase cassette, dfrXV, inserted in a class 1 integron . Antimicrob Agents Chemother 1998 ; 42 : 2221 – 4 . Google Scholar PubMed 5 Moura A , Soares M , Pereira C et al. INTEGRALL: a database and search engine for integrons, integrases and gene cassettes . Bioinformatics 2009 ; 25 : 1096 – 8 . Google Scholar CrossRef Search ADS PubMed 6 Carattoli A , Aschbacher R , March A et al. Complete nucleotide sequence of the IncN plasmid pKOX105 encoding VIM-1, QnrS1 and SHV-12 proteins in Enterobacteriaceae from Bolzano, Italy compared with IncN plasmids encoding KPC enzymes in the USA . J Antimicrob Chemother 2010 ; 65 : 2070 – 5 . Google Scholar CrossRef Search ADS PubMed 7 L'Abée-Lund TM , Sorum H. Functional Tn5393-like transposon in the R plasmid pRAS2 from the fish pathogen Aeromonas salmonicida subspecies salmonicida isolated in Norway . Appl Environ Microbiol 2000 ; 66 : 5533 – 5 . Google Scholar CrossRef Search ADS PubMed 8 Pai H , Jacoby GA. Sequences of the NPS-1 and TLE-1 β-lactamase genes . Antimicrob Agents Chemother 2001 ; 45 : 2947 – 8 . Google Scholar CrossRef Search ADS PubMed 9 Sullivan MJ , Petty NK , Beatson SA. Easyfig: a genome comparison visualizer . Bioinformatics 2011 ; 27 : 1009 – 10 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Nucleotide sequence analysis of NPS-1 β-lactamase and a novel integron (In1427)-carrying transposon in an MDR Pseudomonas aeruginosa keratitis strain

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Abstract

Sir, The gene encoding NPS-1 β-lactamase (blaNPS-1) was first reported on a self-transmissible plasmid of clinical isolates of Pseudomonas aeruginosa.1 The enzyme can hydrolyse carbenicillin, azlocillin, cefoperazone and cefsulodin, but cannot effectively hydrolyse more stable β-lactams (cefotaxime, ceftazidime, ceftriaxone, monobactam and imipenem).1 Furthermore, blaNPS-1 was encoded on a mobile element of a large conjugative plasmid (pB4) isolated from an activated sludge,2 which shows that blaNPS-1 may rapidly transfer between different species from different sources. In the current study, we report an NPS-1-associated Tn3-like complex transposon in a microbial keratitis isolate of P. aeruginosa. An MDR P. aeruginosa strain (PA34) was isolated from a microbial keratitis patient in India (MIC in Table S1, available as Supplementary data at JAC Online). WGS was performed using MiSeq (Illumina, San Diego, CA, USA) generating 300 bp paired-end reads and a Nextera XT DNA library preparation kit (Illumina) was used to prepare the library. CLC Genomics Workbench 10.0 (QIAGEN Bioinformatics, Aarhus, Denmark) was used to assemble the raw reads. A total of 2 365 558 trimmed reads were assembled into 75 contigs >10 kb with an average coverage of 85×. The nucleotide sequence of the transposon is available under the GenBank® accession number MF487840. Itinerary BLASTn® has revealed that the draft genome of PA34 carries a class 1 integron that is located within a Tn3-like transposon.3 The integron has a locus containing two gene cassettes comprising genes for trimethoprim (dfrA15) and chloramphenicol (cmlA1) resistance. Analysis of the nucleotide sequence flanking these two cassettes revealed important characteristics of gene cassettes which included attC sequences downstream of the dfrA15 and cmlA1 genes. See Figure 1(a and b). The dfrA15 of PA34 is identical to that of many enteric bacteria,4 suggesting this may be their source of origin. Furthermore, the cmlA1 gene was similar to a chromosomal chloramphenicol efflux transporter (U12338.3). This indicates that acquisition of a chromosomal gene may have occurred in the integron as a gene cassette. As trimethoprim and chloramphenicol are not a choice in treatment regimens for P. aeruginosa infections owing to its natural resistance, the presence of dfrA15 and cmlA1 gene cassettes may be of less concern. However, their presence in isolates from the eye, which is a site of interaction of a heterogeneous microbial community, may indicate the potential source of transferable resistance traits. This integron has a new array of gene cassettes and was named In1427, a novel class I integron.5 A characteristic orf5 of the integron was truncated by IS6100, which has also been reported to disrupt an integron in Klebsiella oxytoca.6 This suggests that IS6100 may be responsible for introduction of In1427 into the transposon of PA34. Figure 1 View largeDownload slide Schematic representation of the features of the Tn3 transposon of PA34. The genes of each segment are shown by arrows, indicating assigned functions and the direction of transcription: grey with black border indicates resistance genes and white with black border indicates genes responsible for transposition. (a) Map of the major features of the complete transposon. Mobile elements are indicated by the lines below the sequence. The black solid triangles at the end of lines indicate a repeat region of the elements. A single triangle appearing on the mobile element line means it is truncated. The dotted line indicates the position of the class 1 integron. The schematic is drawn to scale by Easyfig9 with minor modification. (b) Details of the arrangement of the resistance gene cassette in the integron (In1427). PintI1, promoter for transcription of gene cassettes; intI1, integrase gene; attI1, integration site; dfrA15, type I dihydrofolate reductase; cmlA1, chloramphenicol transporter; attC, cassette boundary (59-base element); qacEΔ1, partially deleted gene that encodes quaternary ammonium compound resistance; sul1, sulphonamide resistance; △orf5, truncated gene of unknown function. Numbers correspond to number of bp (map not drawn to scale). (c) A genetic map of Tn5393c of Aeromonas salmonicida subsp. salmonicida (AF262622.1) (5670 bp) and the homologous structure in Tn3-like transposon of PA34. The segment in the rectangular box represents genes inserted in the original structure of Tn5393c and the downward arrow indicates the location of homologous genes. (d) The genetic environment of the blaNPS-1 gene region from plasmid pB4. Numbers correspond to number of bp. Figure 1 View largeDownload slide Schematic representation of the features of the Tn3 transposon of PA34. The genes of each segment are shown by arrows, indicating assigned functions and the direction of transcription: grey with black border indicates resistance genes and white with black border indicates genes responsible for transposition. (a) Map of the major features of the complete transposon. Mobile elements are indicated by the lines below the sequence. The black solid triangles at the end of lines indicate a repeat region of the elements. A single triangle appearing on the mobile element line means it is truncated. The dotted line indicates the position of the class 1 integron. The schematic is drawn to scale by Easyfig9 with minor modification. (b) Details of the arrangement of the resistance gene cassette in the integron (In1427). PintI1, promoter for transcription of gene cassettes; intI1, integrase gene; attI1, integration site; dfrA15, type I dihydrofolate reductase; cmlA1, chloramphenicol transporter; attC, cassette boundary (59-base element); qacEΔ1, partially deleted gene that encodes quaternary ammonium compound resistance; sul1, sulphonamide resistance; △orf5, truncated gene of unknown function. Numbers correspond to number of bp (map not drawn to scale). (c) A genetic map of Tn5393c of Aeromonas salmonicida subsp. salmonicida (AF262622.1) (5670 bp) and the homologous structure in Tn3-like transposon of PA34. The segment in the rectangular box represents genes inserted in the original structure of Tn5393c and the downward arrow indicates the location of homologous genes. (d) The genetic environment of the blaNPS-1 gene region from plasmid pB4. Numbers correspond to number of bp. The transposon also possesses three other antibiotic resistance genes: two aminoglycoside-modifying enzymes (AMEs) and one β-lactamase (NPS-1) (Figure 1a). The first AME is APH(3’’)-Ib, identical to strA from Pseudomonas sp. B13, and the second AME is APH(6)-Id, identical to strB from Mycobacterium abscessus subsp. bolletii F1725 plasmid BRA100. Tauch et al.2 have described that the strA–strB gene pair in Tn5393c was highly transferable among bacteria isolated from plants, animals and humans. However, the original structure of Tn5393c, which was found first in the R plasmid pRAS2 from the fish pathogen Aeromonas salmonicida subsp. salmonicida (AF262622.1),7 was interrupted in PA34 by a 5735 bp region that also included another resistance gene (blaNPS-1). The segment was inserted between the tnpR and strA–strB pairs (Figure 1c). An ISPsy42 (Tn3 family) was found in the region between 9711 and 15 439 bp of the transposon. This suggests that Tn5393c may have the capacity to be integrated by other mobile elements that may be incorporated into resistance genes (blaNPS-1 in this case). A putative mobile element (Tn6205) was found between two resolvase genes and was associated with the strA, strB and blaNPS-1 genes (Figure 1a). The Tn6205 also disrupted the second tnpA. This genetic organization of a Tn3-like transposon of PA34 suggests that insertion and recombination of antibiotic resistance genes may have occurred in multiple steps and dissemination of antibiotic resistance may have occurred between distantly related bacteria. blaNPS-1 was inserted between tnpR and strA and its genetic environment is different in PA34 than that previously reported in the plasmid pB42 (Figure 1d). In PA34, blaNPS-1 is associated with Tn3-like transposons along with aminoglycoside resistance genes. This suggests that blaNPS-1 can be found in different genetic environments and may have different sources in the environment. The nucleotide sequence of blaNPS-1 was 100% similar to plasmid pMLH50 (from a clinical isolate),8 but only 99.74% similar to plasmid pB4 (from environmental isolates)2 and a draft genome sequence of Pseudomonas stutzeri 40D2 (MWUI01000033.1) (M. S. R. Shuvo, S. Bashar, M. Karmaker, N. Chauhan, P. Nilawe, M. Sultana and M. A. Hossain, unpublished data). This suggests that blaNPS-1 is circulating in environmental resistance gene pools and can be acquired and maintained in clinical isolates. Further research will help ascertain the exact location of the transposon in the PA34 genome. In conclusion, the current study shows that an ocular isolate of P. aeruginosa may act as a reservoir of resistance genes. Acknowledgements We would like to acknowledge the Singapore Centre for Environmental Life Sciences Engineering (SCELSE), whose research is supported by the National Research Foundation Singapore, Ministry of Education, Nanyang Technological University and National University of Singapore, under its Research Centre of Excellence Programme. Sequencing of DNA was carried out with the help of Daniela Moses and Stephan Schuster using the sequencing facilities at SCELSE. Funding Funding was provided by the School of Optometry and Vision Science, University of New South Wales. Transparency declarations None to declare. Supplementary data Table S1 is available as Supplementary data at JAC Online. References 1 Livermore DM , Jones CS. Characterization of NPS-1, a novel plasmid-mediated β-lactamase, from two Pseudomonas aeruginosa isolates . Antimicrob Agents Chemother 1986 ; 29 : 99 – 103 . Google Scholar CrossRef Search ADS PubMed 2 Tauch A , Schluter A , Bischoff N et al. The 79,370-bp conjugative plasmid pB4 consists of an IncP-1β backbone loaded with a chromate resistance transposon, the strA-strB streptomycin resistance gene pair, the oxacillinase gene blaNPS-1, and a tripartite antibiotic efflux system of the resistance-nodulation-division family . Mol Genet Genomics 2003 ; 268 : 570 – 84 . Google Scholar PubMed 3 Kung VL , Ozer EA , Hauser AR. The accessory genome of Pseudomonas aeruginosa . Microbiol Mol Biol Rev 2010 ; 74 : 621 – 41 . Google Scholar CrossRef Search ADS PubMed 4 Adrian PV , du Plessis M , Klugman KP et al. New trimethoprim-resistant dihydrofolate reductase cassette, dfrXV, inserted in a class 1 integron . Antimicrob Agents Chemother 1998 ; 42 : 2221 – 4 . Google Scholar PubMed 5 Moura A , Soares M , Pereira C et al. INTEGRALL: a database and search engine for integrons, integrases and gene cassettes . Bioinformatics 2009 ; 25 : 1096 – 8 . Google Scholar CrossRef Search ADS PubMed 6 Carattoli A , Aschbacher R , March A et al. Complete nucleotide sequence of the IncN plasmid pKOX105 encoding VIM-1, QnrS1 and SHV-12 proteins in Enterobacteriaceae from Bolzano, Italy compared with IncN plasmids encoding KPC enzymes in the USA . J Antimicrob Chemother 2010 ; 65 : 2070 – 5 . Google Scholar CrossRef Search ADS PubMed 7 L'Abée-Lund TM , Sorum H. Functional Tn5393-like transposon in the R plasmid pRAS2 from the fish pathogen Aeromonas salmonicida subspecies salmonicida isolated in Norway . Appl Environ Microbiol 2000 ; 66 : 5533 – 5 . Google Scholar CrossRef Search ADS PubMed 8 Pai H , Jacoby GA. Sequences of the NPS-1 and TLE-1 β-lactamase genes . Antimicrob Agents Chemother 2001 ; 45 : 2947 – 8 . Google Scholar CrossRef Search ADS PubMed 9 Sullivan MJ , Petty NK , Beatson SA. Easyfig: a genome comparison visualizer . Bioinformatics 2011 ; 27 : 1009 – 10 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Journal of Antimicrobial ChemotherapyOxford University Press

Published: Mar 13, 2018

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