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A Novel SXT/R391 Integrative and Conjugative Element Carries Two Copies of the bla_NDM-1 Gene in Proteus mirabilis.

ABSTRACT: The rapid spread of the bla_NDM-1 gene is a major public health concern. Here, we describe the multidrug-resistant Proteus mirabilis strain XH1653, which contains a novel SXT/R391 integrative and conjugative element (ICE), harboring two tandem copies of bla_NDM-1 and 21 other resistance genes. XH1653 was resistant to all antibiotics tested, apart from aztreonam. Whole-genome data revealed that two copies of bla_NDM-1 embedded in the ISCR1 element are located in HS4 of the novel ICE, which we named ICEPmiChnXH1653. A circular intermediate of ICEPmiChnXH1653 was detected by PCR, and conjugation experiments showed that the ICE can be transferred to the Escherichia coli strain EC600 with frequencies of 1.5 × 10^-7. In the recipient strain, the ICE exhibited a higher excision frequency and extrachromosomal copy number than the ICE in the donor strain. We also observed that the presence of ICEPmiChnXH1653 has a negative impact on bacterial fitness and leads to changes in the transcriptome of the host. In vitro evolution experiments under nonselective conditions showed that the two tandem copies of the ISCR1 element and the ISVsa3 element can be lost during repeated laboratory passage. This is the first report of a novel SXT/R391 ICE carrying two tandem copies of bla_NDM-1, which also illustrates the role that ICEs may play as platforms for the accumulation and transmission of antibiotic resistance genes. IMPORTANCE The occurrence of carbapenemase-producing Proteus mirabilis, especially those strains producing NDM-1 and its variants, is a major public health concern worldwide. The integrative conjugative element (ICE) plays an important role in horizontal acquisition of resistance genes. In this study, we characterized a novel SXT/R391 ICE from a clinical P. mirabilis isolate that we named ICEPmiChnXH1653, which contains two tandem copies of the carbapenemase gene bla_NDM-1. We performed an integrative approach to gain insights into different aspects of ICEPmiChnXH1653 evolution and biology and observed that ICEPmiChnXH1653 obtained the carbapenemase gene bla_NDM-1 by ISCR1-mediated homologous recombination. Our study reveals that the transmission of bla_NDM-1 by ISCR1 elements or ICEs may be an important contributor to the carbapenem resistance development across species, which could improve our understanding of horizontal gene transfer in clinical environments.

SUBMITTER: He J

PROVIDER: S-EPMC8386438 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Proteus mirabilis can transfer transposons, insertion sequences, and gene cassettes to the chromosomes of other hosts through SXT/R391 integrative and conjugative elements (ICEs), significantly increasing the possibility of antibiotic resistance gene (ARG) evolution and expanding the risk of ARGs transmission among bacteria. A total of 103 strains of P. mirabilis were isolated from 25 farms in China from 2018 to 2020. The positive detection rate of SXT/R391 ICEs was 25.2% (26/103). All SXT/R391 ICEs positive P. mirabilis exhibited a high level of overall drug resistance. Conjugation experiments showed that all 26 SXT/R391 ICEs could efficiently transfer to Escherichia coli EC600 with a frequency of 2.0 × 10-7 to 6.0 × 10-5. The acquired ARGs, genetic structures, homology relationships, and conservation sequences of 26 (19 different subtypes) SXT/R391 ICEs were investigated by high-throughput sequencing, whole-genome typing, and phylogenetic tree construction. ICEPmiChnHBRJC2 carries erm (42), which have never been found within an SXT/R391 ICE in P. mirabilis, and ICEPmiChnSC1111 carries 19 ARGs, including clinically important cfr, blaCTX-M-65, and aac(6')-Ib-cr, making it the ICE with the most ARGs reported to date. Through genetic stability, growth curve, and competition experiments, it was found that the transconjugant of ICEPmiChnSCNNC12 did not have a significant fitness cost on the recipient bacterium EC600 and may have a higher risk of transmission and dissemination. Although the transconjugant of ICEPmiChnSCSZC20 had a relatively obvious fitness cost on EC600, long-term resistance selection pressure may improve bacterial fitness through compensatory adaptation, providing scientific evidence for risk assessment of horizontal transfer and dissemination of SXT/R391 ICEs in P. mirabilis.IMPORTANCEThe spread of antibiotic resistance genes (ARGs) is a major public health concern. The study investigated the prevalence and genetic diversity of integrative and conjugative elements (ICEs) in Proteus mirabilis, which can transfer ARGs to other hosts. The study found that all of the P. mirabilis strains carrying ICEs exhibited a high level of drug resistance and a higher risk of transmission and dissemination of ARGs. The analysis of novel multidrug-resistant ICEs highlighted the potential for the evolution and spread of novel resistance mechanisms. These findings emphasize the importance of monitoring the spread of ICEs carrying ARGs and the urgent need for effective strategies to combat antibiotic resistance. Understanding the genetic diversity and potential for transmission of ARGs among bacteria is crucial for developing targeted interventions to mitigate the threat of antibiotic resistance.

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A Novel SXT/R391 Integrative and Conjugative Element Carries Two Copies of the bla_NDM-1 Gene in Proteus mirabilis.

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A Novel SXT/R391 Integrative and Conjugative Element Carries Two Copies of the blaNDM-1 Gene in Proteus mirabilis.

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OmicsDI is part of the ELIXIR infrastructure

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A Novel SXT/R391 Integrative and Conjugative Element Carries Two Copies of the bla_NDM-1 Gene in Proteus mirabilis.