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Abstract

The ICEKp258.2 genomic island (GI) has been proposed as an important factor for the emergence and success of the globally spread carbapenem-resistant sequence type (ST) 258. However, a characterization of this horizontally acquired element is lacking. Using bioinformatic and experimental approaches, we found that ICEKp258.2 is not confined to ST258 and ST512, but also carried by ST3795 strains and emergent invasive multidrug-resistant pathogens from ST1519. We also identified several ICEKp258.2-like GIs spread among different STs, other species and even other pathogen genera, uncovering horizontal gene transfer events between different STs and bacterial genera. Also, the comparative and phylogenetic analyses of the ICEKp258.2-like GIs revealed that the most closely related ICEKp258.2-like GIs were harboured by ST11 strains. Importantly, we found that subinhibitory concentrations of antibiotics used in treating infections can induce the excision of this GI and modulate its gene expression. Our findings provide the basis for the study of ICEKp258.2 and its role in the success of ST258. They also highlight the potential role of antibiotics in the spread of ICEKp258.2-like GIs among bacterial pathogens.

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2023-12-11
2024-11-10
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References

  1. Antimicrobial Resistance Collaborators Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 2022; 399:629–655
    [Google Scholar]
  2. Gonzalez-Ferrer S, Peñaloza HF, Budnick JA, Bain WG, Nordstrom HR et al. Finding order in the chaos: outstanding questions in Klebsiella pneumoniae pathogenesis. Infect Immun 2021; 89:e00693-20 [View Article] [PubMed]
    [Google Scholar]
  3. Zhen X, Stålsby Lundborg C, Sun X, Gu S, Dong H. Clinical and economic burden of carbapenem-resistant infection or colonization caused by Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii: a multicenter study in China. Antibiotics 2020; 9:514 [View Article] [PubMed]
    [Google Scholar]
  4. Wang M, Earley M, Chen L, Hanson BM, Yu Y et al. Clinical outcomes and bacterial characteristics of carbapenem-resistant Klebsiella pneumoniae complex among patients from different global regions (CRACKLE-2): a prospective, multicentre, cohort study. Lancet Infect Dis 2022; 22:401–412 [View Article] [PubMed]
    [Google Scholar]
  5. Hennart M, Guglielmini J, Bridel S, Maiden MCJ, Jolley KA et al. A dual barcoding approach to bacterial strain nomenclature: genomic taxonomy of Klebsiella pneumoniae strains. Mol Biol Evol 2022; 39:msac135 [View Article] [PubMed]
    [Google Scholar]
  6. David S, Cohen V, Reuter S, Sheppard AE, Giani T et al. Integrated chromosomal and plasmid sequence analyses reveal diverse modes of carbapenemase gene spread among Klebsiella pneumoniae. Proc Natl Acad Sci USA 2020; 117:25043–25054 [View Article] [PubMed]
    [Google Scholar]
  7. Bowers JR, Kitchel B, Driebe EM, MacCannell DR, Roe C et al. Genomic analysis of the emergence and rapid global dissemination of the clonal group 258 Klebsiella pneumoniae pandemic. PLoS One 2015; 10:e0133727 [View Article] [PubMed]
    [Google Scholar]
  8. Lee C-R, Lee JH, Park KS, Kim YB, Jeong BC et al. Global dissemination of Klebsiella pneumoniae: epidemiology, genetic context, treatment options, and detection methods. Front Microbiol 2016; 7:895
    [Google Scholar]
  9. Baker S, Thomson N, Weill F-X, Holt KE. Genomic insights into the emergence and spread of antimicrobial-resistant bacterial pathogens. Science 2017; 360:733–738 [View Article] [PubMed]
    [Google Scholar]
  10. Chen L, Mathema B, Chavda KD, DeLeo FR, Bonomo RA et al. Carbapenemase-producing Klebsiella pneumoniae: molecular and genetic decoding. Trends Microbiol 2014; 22:686–696 [View Article] [PubMed]
    [Google Scholar]
  11. Ahn D, Bhushan G, McConville TH, Annavajhala MK, Soni RK et al. An acquired acyltransferase promotes Klebsiella pneumoniae ST258 respiratory infection. Cell Rep 2021; 35:109196 [View Article] [PubMed]
    [Google Scholar]
  12. Chen L, Mathema B, Pitout JDD, DeLeo FR, Kreiswirth BN. Epidemic Klebsiella pneumoniae ST258 is a hybrid strain. mBio 2014; 5:e01355-14 [View Article] [PubMed]
    [Google Scholar]
  13. Zhang X, Wang W, Yu H, Wang M, Zhang H et al. New Delhi metallo-β-lactamase 5-producing Klebsiella pneumoniae sequence type 258, Southwest China, 2017. Emerg Infect Dis 2019; 25:1209–1213 [View Article] [PubMed]
    [Google Scholar]
  14. Doménech-Sánchez A, Martínez-Martínez L, Hernández-Allés S, del Carmen Conejo M, Pascual A et al. Role of Klebsiella pneumoniae OmpK35 porin in antimicrobial resistance. Antimicrob Agents Chemother 2003; 47:3332–3335 [View Article] [PubMed]
    [Google Scholar]
  15. Deleo FR, Chen L, Porcella SF, Martens CA, Kobayashi SD et al. Molecular dissection of the evolution of carbapenem-resistant multilocus sequence type 258 Klebsiella pneumoniae. Proc Natl Acad Sci USA 2014; 111:4988–4993 [View Article] [PubMed]
    [Google Scholar]
  16. Tzouvelekis LS, Miriagou V, Kotsakis SD, Spyridopoulou K, Athanasiou E et al. KPC-producing, multidrug-resistant Klebsiella pneumoniae sequence type 258 as a typical opportunistic pathogen. Antimicrob Agents Chemother 2013; 57:5144–5146 [View Article] [PubMed]
    [Google Scholar]
  17. Peñaloza HF, Ahn D, Schultz BM, Piña-Iturbe A, González LA et al. L-Arginine enhances intracellular killing of carbapenem-resistant Klebsiella pneumoniae ST258 by murine neutrophils. Front Cell Infect Microbiol 2020; 10:571771 [View Article] [PubMed]
    [Google Scholar]
  18. Adler A, Khabra E, Chmelnitsky I, Giakkoupi P, Vatopoulos A et al. Development and validation of a multiplex PCR assay for identification of the epidemic ST-258/512 KPC-producing Klebsiella pneumoniae clone. Diagn Microbiol Infect Dis 2014; 78:12–15 [View Article] [PubMed]
    [Google Scholar]
  19. Piña-Iturbe A, Ulloa-Allendes D, Pardo-Roa C, Coronado-Arrázola I, Salazar-Echegarai FJ et al. Comparative and phylogenetic analysis of a novel family of Enterobacteriaceae-associated genomic islands that share a conserved excision/integration module. Sci Rep 2018; 8:10292 [View Article] [PubMed]
    [Google Scholar]
  20. Brettin T, Davis JJ, Disz T, Edwards RA, Gerdes S et al. RASTtk: a modular and extensible implementation of the RAST algorithm for building custom annotation pipelines and annotating batches of genomes. Sci Rep 2015; 5:8365 [View Article] [PubMed]
    [Google Scholar]
  21. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol 1990; 215:403–410 [View Article] [PubMed]
    [Google Scholar]
  22. Darling AE, Mau B, Perna NT. progressiveMauve: multiple genome alignment with gene gain, loss and rearrangement. PLoS One 2010; 5:e11147 [View Article] [PubMed]
    [Google Scholar]
  23. Sullivan MJ, Petty NK, Beatson SA. Easyfig: a genome comparison visualizer. Bioinformatics 2011; 27:1009–1010 [View Article] [PubMed]
    [Google Scholar]
  24. Johnson M, Zaretskaya I, Raytselis Y, Merezhuk Y, McGinnis S et al. NCBI BLAST: a better web interface. Nucleic Acids Res 2008; 36:W5–W9 [View Article] [PubMed]
    [Google Scholar]
  25. Jolley KA, Bray JE, Maiden MCJ. Open-access bacterial population genomics: BIGSdb software, the PubMLST.org website and their applications. Wellcome Open Res 2018; 3:124 [View Article] [PubMed]
    [Google Scholar]
  26. Zhou Z, Alikhan N-F, Sergeant MJ, Luhmann N, Vaz C et al. GrapeTree: visualization of core genomic relationships among 100,000 bacterial pathogens. Genome Res 2018; 28:1395–1404 [View Article] [PubMed]
    [Google Scholar]
  27. Edgar RC. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 2004; 32:1792–1797 [View Article] [PubMed]
    [Google Scholar]
  28. Kumar S, Stecher G, Li M, Knyaz C, Tamura K. MEGA X: Molecular Evolutionary Genetics Analysis across computing platforms. Mol Biol Evol 2018; 35:1547–1549 [View Article] [PubMed]
    [Google Scholar]
  29. Trifinopoulos J, Nguyen L-T, von Haeseler A, Minh BQ. W-IQ-TREE: a fast online phylogenetic tool for maximum likelihood analysis. Nucleic Acids Res 2016; 44:W232–W235 [View Article] [PubMed]
    [Google Scholar]
  30. Piña-Iturbe A, Hoppe-Elsholz G, Fernández PA, Santiviago CA, González PA et al. Bioinformatic and experimental characterization of SEN1998: a conserved gene carried by the Enterobacteriaceae-associated ROD21-like family of genomic islands. Sci Rep 2022; 12:2435 [View Article] [PubMed]
    [Google Scholar]
  31. Marcoleta AE, Berríos-Pastén C, Nuñez G, Monasterio O, Lagos R. Klebsiella pneumoniae asparagine tDNAs are integration hotspots for different genomic Islands encoding microcin E492 production determinants and other putative virulence factors present in hypervirulent strains. Front Microbiol 2016; 7:849 [View Article] [PubMed]
    [Google Scholar]
  32. Berríos-Pastén C, Acevedo R, Arros P, Varas MA, Wyres KL et al. Properties of genes encoding transfer RNAs as integration sites for genomic islands and prophages in Klebsiella pneumoniae. bioRxiv 2020365908 [View Article]
    [Google Scholar]
  33. Tobar HE, Salazar-Echegarai FJ, Nieto PA, Palavecino CE, Sebastian VP et al. Chromosomal excision of a new pathogenicity island modulates Salmonella virulence in vivo. Curr Gene Ther 2013; 13:240–249 [View Article] [PubMed]
    [Google Scholar]
  34. Salazar-Echegarai FJ, Tobar HE, Nieto PA, Riedel CA, Bueno SM. Conjugal transfer of the pathogenicity island ROD21 in Salmonella enterica serovar Enteritidis depends on environmental conditions. PLoS One 2014; 9:e90626 [View Article] [PubMed]
    [Google Scholar]
  35. Pardo-Roa C, Salazar GA, Noguera LP, Salazar-Echegarai FJ, Vallejos OP et al. Pathogenicity island excision during an infection by Salmonella enterica serovar Enteritidis is required for crossing the intestinal epithelial barrier in mice to cause systemic infection. PLoS Pathog 2019; 15:e1008152 [View Article] [PubMed]
    [Google Scholar]
  36. Ching C, Orubu ESF, Sutradhar I, Wirtz VJ, Boucher HW et al. Bacterial antibiotic resistance development and mutagenesis following exposure to subinhibitory concentrations of fluoroquinolones in vitro: a systematic review of the literature. JAC Antimicrob Resist 2020; 2:dlaa068 [View Article] [PubMed]
    [Google Scholar]
  37. Cázares-Domínguez V, Ochoa SA, Cruz-Córdova A, Rodea GE, Escalona G et al. Vancomycin modifies the expression of the agr system in multidrug-resistant Staphylococcus aureus clinical isolates. Front Microbiol 2015; 6:369 [View Article] [PubMed]
    [Google Scholar]
  38. de Andrade JPL, de Macêdo Farias L, Ferreira JFG, Bruna-Romero O, da Glória de Souza D et al. Sub-inhibitory concentration of piperacillin-tazobactam may be related to virulence properties of filamentous Escherichia coli. Curr Microbiol 2016; 72:19–28 [View Article] [PubMed]
    [Google Scholar]
  39. Opoku-Temeng C, Freedman B, Porter AR, Kobayashi SD, Chen L et al. Subinhibitory concentrations of antibiotics alter the response of Klebsiella pneumoniae to components of innate host defense. Microbiol Spectr 2022; 10:e0151722 [View Article] [PubMed]
    [Google Scholar]
  40. Beaber JW, Hochhut B, Waldor MK. SOS response promotes horizontal dissemination of antibiotic resistance genes. Nature 2004; 427:72–74 [View Article] [PubMed]
    [Google Scholar]
  41. Liu P, Wu Z, Xue H, Zhao X. Antibiotics trigger initiation of SCCmec transfer by inducing SOS responses. Nucleic Acids Res 2017; 45:3944–3952 [View Article] [PubMed]
    [Google Scholar]
  42. Chittò M, Berger M, Klotz L, Dobrindt U. Sub-inhibitory concentrations of SOS-response inducing antibiotics stimulate integrase expression and excision of pathogenicity islands in uropathogenic Escherichia coli strain 536. Int J Med Microbiol 2020; 310:151361 [View Article] [PubMed]
    [Google Scholar]
  43. Silva CA, Blondel CJ, Quezada CP, Porwollik S, Andrews-Polymenis HL et al. Infection of mice by Salmonella enterica serovar Enteritidis involves additional genes that are absent in the genome of serovar Typhimurium. Infect Immun 2012; 80:839–849 [View Article] [PubMed]
    [Google Scholar]
  44. Centonze AR, Azzini AM, Mazzi R, Merighi M, Concia E et al. Klebsiella pneumoniae (ST1519) producing KPC-19 carbapenemase in a patient undergoing selective digestive decontamination before liver transplantation. Clin Microbiol Infect 2018; 24:203–204 [View Article] [PubMed]
    [Google Scholar]
  45. Gaibani P, Campoli C, Lewis RE, Volpe SL, Scaltriti E et al. In vivo evolution of resistant subpopulations of KPC-producing Klebsiella pneumoniae during ceftazidime/avibactam treatment. J Antimicrob Chemother 2018; 73:1525–1529 [View Article] [PubMed]
    [Google Scholar]
  46. Gaibani P, Re MC, Campoli C, Viale PL, Ambretti S. Bloodstream infection caused by KPC-producing Klebsiella pneumoniae resistant to ceftazidime/avibactam: epidemiology and genomic characterization. Clin Microbiol Infect 2020; 26:516 [View Article] [PubMed]
    [Google Scholar]
  47. Gaibani P, Ambretti S, Campoli C, Viale P, Re MC. Genomic characterization of a Klebsiella pneumoniae ST1519 resistant to ceftazidime/avibactam carrying a novel KPC variant (KPC-36). Int J Antimicrob Agents 2020; 55:2019–2021 [View Article] [PubMed]
    [Google Scholar]
  48. Chen L, Chavda KD, Mediavilla JR, Zhao Y, Fraimow HS et al. Multiplex real-time PCR for detection of an epidemic KPC-producing Klebsiella pneumoniae ST258 clone. Antimicrob Agents Chemother 2012; 56:3444–3447 [View Article] [PubMed]
    [Google Scholar]
  49. Lin H-H, Chen Y-S, Hsiao H-W, Hsueh P-T, Ni W-F et al. Two genome sequences of Klebsiella pneumoniae strains with sequence type 23 and capsular serotype K1. Genome Announc 2016; 4:e01097-16 [View Article] [PubMed]
    [Google Scholar]
  50. Umeda K, Nakamura H, Fukuda A, Matsumoto Y, Motooka D et al. Genomic characterization of clinical Enterobacter roggenkampii co-harbouring blaIMP-1- and blaGES-5-encoding IncP6 and mcr-9-encoding IncHI2 plasmids isolated in Japan. J Glob Antimicrob Resist 2021; 24:220–227 [View Article] [PubMed]
    [Google Scholar]
  51. Ramsay JP, Sullivan JT, Stuart GS, Lamont IL, Ronson CW. Excision and transfer of the Mesorhizobium loti R7A symbiosis island requires an integrase IntS, a novel recombination directionality factor RdfS, and a putative relaxase RlxS. Mol Microbiol 2006; 62:723–734 [View Article] [PubMed]
    [Google Scholar]
  52. Almagro-Moreno S, Napolitano MG, Boyd EF. Excision dynamics of Vibrio pathogenicity island-2 from Vibrio cholerae: role of a recombination directionality factor VefA. BMC Microbiol 2010; 10:306 [View Article] [PubMed]
    [Google Scholar]
  53. Vanga BR, Ramakrishnan P, Butler RC, Toth IK, Ronson CW et al. Mobilization of horizontally acquired island 2 is induced in planta in the phytopathogen Pectobacterium atrosepticum SCRI1043 and involves the putative relaxase ECA0613 and quorum sensing. Environ Microbiol 2015; 17:4730–4744 [View Article] [PubMed]
    [Google Scholar]
  54. Poulin-Laprade D, Matteau D, Jacques P-É, Rodrigue S, Burrus V. Transfer activation of SXT/R391 integrative and conjugative elements: unraveling the SetCD regulon. Nucleic Acids Res 2015; 43:2045–2056 [View Article] [PubMed]
    [Google Scholar]
  55. Dwyer DJ, Belenky PA, Yang JH, MacDonald IC, Martell JD et al. Antibiotics induce redox-related physiological alterations as part of their lethality. Proc Natl Acad Sci USA 2014; 111:E2100–E2109 [View Article] [PubMed]
    [Google Scholar]
  56. McConville TH, Giddins MJ, Uhlemann A-C. An efficient and versatile CRISPR-Cas9 system for genetic manipulation of multi-drug resistant Klebsiella pneumoniae. STAR Protoc 2021; 2:100373 [View Article] [PubMed]
    [Google Scholar]
  57. Balasubramanian D, López-Pérez M, Grant T-A, Ogbunugafor CB, Almagro-Moreno S. Molecular mechanisms and drivers of pathogen emergence. Trends Microbiol 2022; 30:898–911 [View Article] [PubMed]
    [Google Scholar]
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