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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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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Kikuchi, Y., Matsui, H., Asami, Y. et al. Landscape of blaNDM genes in Enterobacteriaceae. J Antibiot 75, 559–566 (2022). https://doi.org/10.1038/s41429-022-00553-3