A preliminary exploration on the mechanism of the carbapenem-resistance transformation of <i>Serratia marcescens in vivo</i>

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Abstract

Background

The infection of carbapenem-resistant organisms was a huge threat to human health due to their global spread. Dealing with a carbapenem-resistant Serratia marcescens (CRSM) infection poses a significant challenge in clinical settings. This study aims to provide insights into strategies for controlling CRSM infection by exploring the transformation mechanism of carbapenem-resistance.

Methods

We used whole genome sequencing (WGS) to investigate the mechanism of carbapenem resistance in 14 S. marcescens isolates in vivo. The expression level of related genes and the minimum inhibitory concentration of meropenem (MIC _MEM) were also evaluated to confirm the mechanism of carbapenem resistance.

Results

Seven groups of S. marcescens, each consisting of two strains, were collected from a hospital and displayed a shift in MIC _MEM from low to high levels. Homology analysis revealed that the isolates in five groups were significantly different from the remaining two. WGS and experimental evidence indicated that four groups of strains developed carbapenem resistance by acquiring the bla _KPC (obtaining group), while two groups (persisting group) increased the expression level of the bla _KPC. In contrast, isolates in the last group (missing group) did not carry the bla _KPC. All strains possessed multiple β-lactamase genes, including bla _CTX−M−14, bla _SRT−1, and bla _SRT−2. However, only in the missing group, the carbapenem-resistant strain lost an outer membrane protein-encoding gene, leading to increased bla _CTX−M−14 expression compared to the carbapenem-susceptible strain.

Conclusion

The study findings suggest that S. marcescens strains developed diverse carbapenem resistance in vivo through the evolution of drug resistance, rather than through clone replacement. We hypothesize that carbapenem resistance in S. marcescens was due to certain clonal types with a distinct mechanism.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12864-023-09904-2.

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Most cited references 23

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Serratia infections: from military experiments to current practice.

Steven Mahlen (2011)

Serratia species, in particular Serratia marcescens, are significant human pathogens. S. marcescens has a long and interesting taxonomic, medical experimentation, military experimentation, and human clinical infection history. The organisms in this genus, particularly S. marcescens, were long thought to be nonpathogenic. Because S. marcescens was thought to be a nonpathogen and is usually red pigmented, the U.S. military conducted experiments that attempted to ascertain the spread of this organism released over large areas. In the process, members of both the public and the military were exposed to S. marcescens, and this was uncovered by the press in the 1970s, leading to U.S. congressional hearings. S. marcescens was found to be a certain human pathogen by the mid-1960s. S. marcescens and S. liquefaciens have been isolated as causative agents of numerous outbreaks and opportunistic infections, and the association of these organisms with point sources such as medical devices and various solutions given to hospitalized patients is striking. Serratia species appear to be common environmental organisms, and this helps to explain the large number of nosocomial infections due to these bacteria. Since many nosocomial infections are caused by multiply antibiotic-resistant strains of S. marcescens, this increases the danger to hospitalized patients, and hospital personnel should be vigilant in preventing nosocomial outbreaks due to this organism. S. marcescens, and probably other species in the genus, carries several antibiotic resistance determinants and is also capable of acquiring resistance genes. S. marcescens and S. liquefaciens are usually identified well in the clinical laboratory, but the other species are rare enough that laboratory technologists may not recognize them. 16S rRNA gene sequencing may enable better identification of some of the less common Serratia species.

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Antibiotic Resistance Mediated by the MacB ABC Transporter Family: A Structural and Functional Perspective

Nicholas Greene, Elise Kaplan, Allister Crow … (2018)

The MacB ABC transporter forms a tripartite efflux pump with the MacA adaptor protein and TolC outer membrane exit duct to expel antibiotics and export virulence factors from Gram-negative bacteria. Here, we review recent structural and functional data on MacB and its homologs. MacB has a fold that is distinct from other structurally characterized ABC transporters and uses a unique molecular mechanism termed mechanotransmission. Unlike other bacterial ABC transporters, MacB does not transport substrates across the inner membrane in which it is based, but instead couples cytoplasmic ATP hydrolysis with transmembrane conformational changes that are used to perform work in the extra-cytoplasmic space. In the MacAB-TolC tripartite pump, mechanotransmission drives efflux of antibiotics and export of a protein toxin from the periplasmic space via the TolC exit duct. Homologous tripartite systems from pathogenic bacteria similarly export protein-like signaling molecules, virulence factors and siderophores. In addition, many MacB-like ABC transporters do not form tripartite pumps, but instead operate in diverse cellular processes including antibiotic sensing, cell division and lipoprotein trafficking.

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Emergence of Serratia marcescens, Klebsiella pneumoniae, and Escherichia coli Isolates possessing the plasmid-mediated carbapenem-hydrolyzing beta-lactamase KPC-2 in intensive care units of a Chinese hospital.

Rong Zhang, Gong Chen, J. Cai … (2008)

Twenty-one Serratia marcescens, ten Klebsiella pneumoniae, and one Escherichia coli isolate with carbapenem resistance or reduced carbapenem susceptibility were recovered from intensive care units (ICUs) in our hospital. Enterobacterial repetitive intergenic consensus-PCR and pulsed-field gel electrophoresis demonstrated that all the S. marcescens isolates belonged to a clonal strain and the 10 K. pneumoniae isolates were indistinguishable or closely related to each other. The MICs of imipenem, meropenem, and ertapenem for all isolates were 2 to 8 microg/ml, except for K. pneumoniae K10 (MICs of 128, 256, and >256 microg/ml). Isoelectric focusing, PCRs, and DNA sequencing indicated that all S. marcescens isolates produced KPC-2 and a beta-lactamase with a pI of 6.5. All K. pneumoniae isolates produced TEM-1, KPC-2, CTX-M-14, and a beta-lactamase with a pI of 7.3. The E. coli E1 isolate produced KPC-2, CTX-M-15, and a beta-lactamase with a pI of 7.3. Conjugation studies with E. coli (EC600) resulted in the transfer of reduced carbapenem susceptibility compared to that of the original isolates, and only the bla(KPC-2) gene was detected in E. coli transconjugants. Plasmid restriction analysis showed identical restriction patterns among all E. coli transconjugants. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and ompK35/36 gene sequence analysis of outer membrane proteins revealed that K. pneumoniae K10 failed to express OmpK36, because of insertional inactivation by an insertion sequence ISEcp1. All these results indicate that KPC-2-producing S. marcescens, K. pneumoniae, and E. coli isolates emerged in ICUs in our hospital. KPC-2 combined with porin deficiency results in high-level carbapenem resistance in K. pneumoniae. The same bla(KPC-2)-encoding plasmid was spread among the three different genera.

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Author and article information

Contributors

Yonghong Xiao: xiaoyonghong@zju.edu.cn

Journal

Journal ID (nlm-ta): BMC Genomics

Journal ID (iso-abbrev): BMC Genomics

Title: BMC Genomics

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2164

Publication date (Electronic): 2 January 2024

Publication date PMC-release: 2 January 2024

Publication date Collection: 2024

Volume: 25

Electronic Location Identifier: 2

Affiliations

[1 ]Laboratory Medicine Center, Department of Transfusion Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang China

[2 ]State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University, ( https://ror.org/00a2xv884) NO.79 Qingchun Road, Hangzhou, 310003 Zhejiang Province China

Article

Publisher ID: 9904

DOI: 10.1186/s12864-023-09904-2

PMC ID: 10759614

SO-VID: be74647c-8425-479b-989d-df2729c48ffd

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 18 June 2023

Date accepted : 14 December 2023

Funding

Funded by: Natural Science Foundation of Zhejiang Province

Award ID: LQ22H190004

Funded by: National Key Research and Development Program of China

Award ID: 2021YFC2300300

Funded by: Fundamental Research Funds for the Central Universities

Award ID: 2022ZFJH003

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: serratia marcescens,carbapenem-resistance,blakpc

Data availability:

ScienceOpen disciplines: Genetics

Keywords: serratia marcescens, carbapenem-resistance, blakpc

A preliminary exploration on the mechanism of the carbapenem-resistance transformation of Serratia marcescens in vivo

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Abstract

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Supplementary Information

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Genome Integrity

Most cited references 23

Serratia infections: from military experiments to current practice.

Antibiotic Resistance Mediated by the MacB ABC Transporter Family: A Structural and Functional Perspective

Emergence of Serratia marcescens, Klebsiella pneumoniae, and Escherichia coli Isolates possessing the plasmid-mediated carbapenem-hydrolyzing beta-lactamase KPC-2 in intensive care units of a Chinese hospital.

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