Nested Russian Doll-like Genetic Mobility Drives Rapid Dissemination of the Carbapenem Resistance Gene bla KPC
Nested Russian Doll-like Genetic Mobility Drives Rapid Dissemination of the Carbapenem Resistance Gene bla KPC
Abstract The recent widespread emergence of carbapenem resistance in Enterobacteriaceae is a major public health concern, as carbapenems are a therapy of last resort in this family of common bacterial pathogens. Resistance genes can mobilize via various mechanisms including conjugation and transposition, however the importance of this mobility in short-term evolution, such as within nosocomial outbreaks, is currently unknown. Using a combination of short- and long-read whole genome sequencing of 281 blaKPC-positive Enterobacteriaceae isolated from a single hospital over five years, we demonstrate rapid dissemination of this carbapenem resistance gene to multiple species, strains, and plasmids. Mobility of blaKPC occurs at multiple nested genetic levels, with transmission of blaKPC strains between individuals, frequent transfer of blaKPC plasmids between strains/species, and frequent transposition of the blaKPC transposon Tn4401 between plasmids. We also identify a common insertion site for Tn4401 within various Tn2-like elements, suggesting that homologous recombination between Tn2-like elements has enhanced the spread of Tn4401 between different plasmid vectors. Furthermore, while short-read sequencing has known limitations for plasmid assembly, various studies have attempted to overcome this with the use of reference-based methods. We also demonstrate that as a consequence of the genetic mobility observed herein, plasmid structures can be extremely dynamic, and therefore these reference-based methods, as well as traditional partial typing methods, can produce very misleading conclusions. Overall, our findings demonstrate that non-clonal resistance gene dissemination can be extremely rapid, presenting significant challenges for public health surveillance and achieving effective control of antibiotic resistance. ImportanceIncreasing antibiotic resistance is a major threat to human health, as highlighted by the recent emergence of multi-drug resistant “superbugs”. Here, we tracked how one important multi-drug resistance gene spread in a single hospital over five years. This revealed high levels of resistance gene mobility to multiple bacterial species, which was facilitated by various different genetic mechanisms. The mobility occurred at multiple nested genetic levels, analogous to a Russian doll set where smaller dolls may be carried along inside larger dolls. Our results challenge traditional views that drug-resistance outbreaks are due to transmission of a single pathogenic strain. Instead, outbreaks can be “gene-based”, and we must therefore focus on tracking specific resistance genes and their context rather than only specific bacteria.
Giess Adam、Mathers AmyJ.、Wilson Daniel J.、the Modernising Medical Microbiology (MMM) Informatics Group、Sheppard Anna E.、Sebra Robert、Cox Heather L.、Grim Christopher J.、Vaughan Alison、Yeh Anthony J.、Stoesser Nicole、Crook Derrick W.、Kasarskis Andrew、Pankhurst Louise J.、Anson Luke W.、Walker A. Sarah、Sifri Costi D.、Peto Tim E.
Modernizing Medical Microbiology Consortium, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford UniversityDivision of Infectious Diseases and International Health, Department of Medicine, University of Virginia Health System||Clinical Microbiology, Department of Pathology, University of Virginia Health SystemModernizing Medical Microbiology Consortium, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford UniversityModernizing Medical Microbiology Consortium, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford UniversityModernizing Medical Microbiology Consortium, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford UniversityIcahn Institute and Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount SinaiDivision of Infectious Diseases and International Health, Department of Medicine, University of Virginia Health SystemFood and Drug AdministrationModernizing Medical Microbiology Consortium, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford UniversityDivision of Infectious Diseases and International Health, Department of Medicine, University of Virginia Health SystemModernizing Medical Microbiology Consortium, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford UniversityModernizing Medical Microbiology Consortium, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford University||Public Health England, Microbiology ServicesIcahn Institute and Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount SinaiModernizing Medical Microbiology Consortium, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford UniversityModernizing Medical Microbiology Consortium, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford UniversityModernizing Medical Microbiology Consortium, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford UniversityDivision of Infectious Diseases and International Health, Department of Medicine, University of Virginia Health System||Office of Hospital Epidemiology, University of Virginia Health SystemModernizing Medical Microbiology Consortium, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford University
医药卫生理论医学研究方法微生物学
Giess Adam,Mathers AmyJ.,Wilson Daniel J.,the Modernising Medical Microbiology (MMM) Informatics Group,Sheppard Anna E.,Sebra Robert,Cox Heather L.,Grim Christopher J.,Vaughan Alison,Yeh Anthony J.,Stoesser Nicole,Crook Derrick W.,Kasarskis Andrew,Pankhurst Louise J.,Anson Luke W.,Walker A. Sarah,Sifri Costi D.,Peto Tim E..Nested Russian Doll-like Genetic Mobility Drives Rapid Dissemination of the Carbapenem Resistance Gene bla KPC[EB/OL].(2025-03-28)[2025-05-17].https://www.biorxiv.org/content/10.1101/033522.点此复制
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