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Landscape of blaNDM genes in Enterobacteriaceae


The blaNDM-1 gene encodes a carbapenemase, New Delhi metallo-β-lactamase (NDM-1), and the ability to produce NDM-1 is spread among Enterobacteriaceae via horizontal gene transfer of plasmids. It has been widely accepted that blaNDM-1 is regulated by a hybrid promoter (PISAba125) consisting of a –10 box from the original blaNDM-1 and a –35 box from ISAba125. However, the conservation of this promoter and the vertical transmission of blaNDM genes by chromosomal integration have not been comprehensively analyzed. We retrieved the region containing the ORF of blaNDM-1 (>95% translated protein identity) and a region 120 bp upstream of the blaNDM-1 start codon from the complete sequence data of Enterobacteriaceae plasmids (n = 10,914) and chromosomes (n = 4908) deposited in GenBank, and the 310 extracted blaNDM genes were analyzed by an in-silico approach. The results showed that most blaNDM genes (99.0%) utilized the promoter, PISAba125. Interestingly, two blaNDM-1 genes from the genus Citrobacter utilized the ISCR1-derived outward-oriented promoters POUT (PISCR1). Furthermore, the insertion of ISAba125 and ISCR1 occurred upstream of the CCATATTT sequence, which is located upstream of the –10 box. We also confirmed that most of the blaNDM genes were disseminated by horizontal gene transfer of the plasmid, but 10 cases of the blaNDM genes were integrated into the chromosome via mobile genetic elements such as IS26, IS150, ISCR1, ICE, and Tn7-like elements. Thus, plasmid-mediated transmission of the PISAba125-blaNDM genes is predominant in Enterobacteriaceae. However, the spread of blaNDM genes with new promoters and vertical dissemination via chromosomal integrations may pose additional serious clinical problems.

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  1. Yong D, et al. Characterization of a new metallo-β-lactamase gene, blaNDM-1, and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Ch. 2009;53:5046–54.

    Article  CAS  Google Scholar 

  2. Acman M, et al. Role of mobile genetic elements in the global dissemination of the carbapenem resistance gene blaNDM. Nat Commun. 2022;13:1131.

    Article  CAS  Google Scholar 

  3. Razavi M, Kristiansson E, Flach C-F, Larsson DGJ. The association between insertion sequences and antibiotic resistance genes. Msphere. 2020;5:e00418–20.

    Article  CAS  Google Scholar 

  4. Bourque G, et al. Ten things you should know about transposable elements. Genome Biol. 2018;19:199.

    Article  CAS  Google Scholar 

  5. Partridge SR, Kwong SM, Firth N, Jensen SO. Mobile genetic elements associated with antimicrobial resistance. Clin Microbiol Rev. 2018;31:e00088–17.

  6. Hernández-Allés S, et al. Development of resistance during antimicrobial therapy caused by insertion sequence interruption of porin genes. Antimicrob Agents Ch. 1999;43:937–9.

    Article  Google Scholar 

  7. Toleman MA, Bennett PM, Walsh TR. ISCR elements: novel gene-capturing systems of the 21st century? Microbiol Mol Biol Rev Mmbr. 2006;70:296–316.

    Article  CAS  Google Scholar 

  8. Lallement C, Pasternak C, Ploy M-C, Jové T. The role of ISCR1-borne POUT promoters in the expression of antibiotic resistance genes. Front Microbiol. 2018;9:2579.

    Article  Google Scholar 

  9. Partridge SR, Iredell JR. Genetic contexts of blaNDM-1. Antimicrob Agents Ch. 2012;56:6065–7.

    Article  CAS  Google Scholar 

  10. Shen W, Le S, Li Y, Hu F. SeqKit: a cross-platform and ultrafast toolkit for FASTA/Q file manipulation. Plos One. 2016;11:e0163962.

    Article  Google Scholar 

  11. Ishikawa J, Hotta K. FramePlot: a new implementation of the frame analysis for predicting protein-coding regions in bacterial DNA with a high G+C content. Fems Microbiol Lett. 1999;174:251–3.

    Article  CAS  Google Scholar 

  12. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing (30th Edition), Clinical and Laboratory Standards Institute, Wayne, PA. M100-ED30 (2020)

  13. Moser A, et al. A patient with multiple carbapenemase producers including an unusual Citrobacter sedlakii hosting an IncC blaNDM-1- and armA-carrying plasmid. Pathogens. Immun. 2021;6:119–34.

    Google Scholar 

  14. Shen P, et al. Detection of an Escherichia coli sequence type 167 strain with two tandem copies of blaNDM-1 in the chromosome. J Clin Microbiol. 2017;55:199–205.

    Article  CAS  Google Scholar 

  15. Luo X, et al. Chromosomal integration of huge and complex blaNDM-carrying genetic elements in Enterobacteriaceae. Front Cell Infect Mi. 2021;11:690799.

    Article  CAS  Google Scholar 

  16. Wozniak RAF, et al. Comparative ICE genomics: insights into the evolution of the SXT/R391 family of ICEs. Plos Genet. 2009;5:e1000786.

    Article  Google Scholar 

  17. Sakamoto N, et al. Genomic characterization of carbapenemase-producing Klebsiella pneumoniae with chromosomally carried blaNDM-1. Antimicrob Agents Ch. 2018;62:e01520–18.

  18. Varani A, He S, Siguier P, Ross K, Chandler M. The IS6 family, a clinically important group of insertion sequences including IS26. Mob DNA. 2021;12:11.

    Article  CAS  Google Scholar 

  19. Ryan MP, Armshaw P, Pembroke JT. SXT/R391 integrative and conjugative elements (ICEs) encode a novel ‘Trap-Door’ strategy for mobile element escape. Front Microbiol. 2016;7:829.

    PubMed  PubMed Central  Google Scholar 

  20. Kuduvalli PN, Rao JE, Craig NL. Target DNA structure plays a critical role in Tn7 transposition. EMBO J. 2001;20:924–32.

    Article  CAS  Google Scholar 

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This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology and the Japan Society for the Promotion of Science (KAKENHI) nos. 19K07542 (to AA), 20K07485 (to AK) and by AMED under Grant Number JP20nk0101552 (to AA) and JP22nk0101587 (to AA). The funders had no role in the study design, date collection or analysis, the decision to publish, or the preparation of manuscript.

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Correspondence to Akio Abe.

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Kikuchi, Y., Matsui, H., Asami, Y. et al. Landscape of blaNDM genes in Enterobacteriaceae. J Antibiot 75, 559–566 (2022).

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