Characterization of a Carbapenem-Resistant Kluyvera Cryocrescens Isolate Carrying Blandm-1 from Hospital Sewage

Carbapenem-resistant Enterobacteriaceae have been a global public health issue in recent years. Here, a carbapenem-resistant Kluyvera cryocrescens strain SCW13 was isolated from hospital sewage, and was then subjected to whole-genome sequencing (WGS). Based on WGS data, antimicrobial resistance genes were identified. Resistance plasmids were completely circularized and further bioinformatics analyses of plasmids were performed. A conjugation assay was performed to identify a self-transmissible plasmid mediating carbapenem resistance. A phylogenetic tree was constructed based on the core genome of publicly available Kluyvera strains. The isolate SCW13 exhibited resistance to cephalosporin and carbapenem. blaNDM-1 was found to be located on a ~53-kb self-transmissible IncX3 plasmid, which exhibited high similarity to the previously reported pNDM-HN380, which is an epidemic blaNDM-1-carrying IncX3 plasmid. Further, we found that SCW13 contained a chromosomal blaKLUC-2 gene, which was the probable origin of the plasmid-born blaKLUC-2 found in Enterobacter cloacae. Phylogenetic analysis showed that K. cryocrescens SCW13 exhibited a close relationship with K. cryocrescens NCTC10483. These findings highlight the further dissemination of blaNDM through clonal IncX3 plasmids related to pNDM-HN380 among uncommon Enterobacteriaceae strains, including Kluyvera in this case.

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Dynamics of blaKPC-2 Dissemination from Non-CG258 Klebsiella pneumoniae to Other Enterobacterales via IncN Plasmids in an Area of High Endemicity

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01743-20 ◽

2020 ◽

Vol 64 (12) ◽

Cited By ~ 1

Author(s):

Ana M. Rada ◽

Elsa De La Cadena ◽

Carlos Agudelo ◽

Cesar Capataz ◽

Nataly Orozco ◽

...

Keyword(s):

Public Health ◽

Klebsiella Pneumoniae ◽

Neonatal Intensive Care ◽

Carbapenem Resistance ◽

Health Interventions ◽

Global Public Health ◽

Public Health Interventions ◽

Content Type ◽

Carbapenem Resistant ◽

Long Read

ABSTRACT Carbapenem-resistant Enterobacterales (CRE) pose a significant threat to global public health. The most important mechanism for carbapenem resistance is the production of carbapenemases. Klebsiella pneumoniae carbapenemase (KPC) represents one of the main carbapenemases worldwide. Complex mechanisms of blaKPC dissemination have been reported in Colombia, a country with a high endemicity of carbapenem resistance. Here, we characterized the dynamics of dissemination of blaKPC gene among CRE infecting and colonizing patients in three hospitals localized in a highly endemic area of Colombia (2013 and 2015). We identified the genomic characteristics of KPC-producing Enterobacterales recovered from patients infected/colonized and reconstructed the dynamics of dissemination of blaKPC-2 using both short and long read sequencing. We found that spread of blaKPC-2 among Enterobacterales in the participating hospitals was due to intra- and interspecies horizontal gene transfer (HGT) mediated by promiscuous plasmids associated with transposable elements that was originated from a multispecies outbreak of KPC-producing Enterobacterales in a neonatal intensive care unit. The plasmids were detected in isolates recovered in other units within the same hospital and nearby hospitals. The gene “epidemic” was driven by IncN-pST15-type plasmids carrying a novel Tn4401b structure and non-Tn4401 elements (NTEKPC) in Klebsiella spp., Escherichia coli, Enterobacter spp., and Citrobacter spp. Of note, mcr-9 was found to coexist with blaKPC-2 in species of the Enterobacter cloacae complex. Our findings suggest that the main mechanism for dissemination of blaKPC-2 is HGT mediated by highly transferable plasmids among species of Enterobacterales in infected/colonized patients, presenting a major challenge for public health interventions in developing countries such as Colombia.

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Uncovering the gut microbiota as a reservoir of ST11 hypervirulent KPC-2-producing Klebsiella pneumoniaeUncovering the gut microbiota as a reservoir of ST11 hypervirulent KPC-2-producing Klebsiella pneumoniae

10.21203/rs.2.17648/v1 ◽

2019 ◽

Author(s):

Beiwen Zheng ◽

Hao Xu ◽

Tao Lv ◽

Lihua Guo ◽

Xiao Yu ◽

...

Keyword(s):

Public Health ◽

Gut Microbiota ◽

Carbapenem Resistance ◽

Underlying Mechanism ◽

Public Health Issue ◽

Virulence Plasmids ◽

Carbapenem Resistant ◽

Health Community ◽

Surgical History ◽

Genomic Characterization

Abstract Background: The emergence and spread of ST11 carbapenem-resistant, hypervirulent K. pneumonia (ST11-CR-HvKP) in China generated great concern from the public health community. The identification of ST11-CR-HvKP strain is expected to become a serious public health issue in China, considering the carbapenem resistance and virulence had converged in an epidemic clone. However, the underlying mechanism that enables its wide dissemination in China remains unclear.Results: Here, we investigate the prevalence of carbapenemase-producing Enterobacteriaceae (CPE) carriage by inpatients in a teaching hospital over a 1-year period, to identify ST11-CR-HvKP reservoirs, and to understand the transmission of these pathogens across healthcare networks. We identified a high colonization prevalence of CPE (12.4%) among inpatients with diarrhea. Correlations were detected between antibiotic exposure, surgical history, and being CPE positive. A genomic investigation of 65 CRKP isolates indicated a shared bacterial population among various wards. Maximum-likelihood phylogenetic tree demonstrated that these isolates were partitioned into three major clades. An analysis of the wzi locus revealed three different K types (KL105, KL47, and K64) among the ST11 isolates, indicating genetic diversity among these isolates. Our review of the cases showed that these patients had no contact with each other, indicating nosocomial transmission. Genetic and sequence mapping revealed complexity in the existence of virulence plasmids and resistance plasmids in the ST11-CRKP isolates. These data indicate that this process was more complicated than was earlier anticipated, as it may have involved multiple ST11 K. pneumoniae lineages and a variety of virulence plasmids. Conclusions: Collectively, this work represents the first evidence of gut microbiota may act as the source of ST11-CR-HvKP isolate. Active surveillance approaches, particularly in ICUs based on the results of this study, should be implemented to combat the spread of ST11-CR-HvKP and to improve patient outcomes. Key words: gut microbiota; hypervirulent; KPC-2; reservoir; genomic characterization

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Dissemination of Blandm-5 in Escherichia Coli via the Incx3 Plasmid From Different Regions in China

10.21203/rs.3.rs-254667/v1 ◽

2021 ◽

Author(s):

Xiaofeng Hu ◽

Lang Yang ◽

Nian Dong ◽

Yanfeng Lin ◽

Ling Zhang ◽

...

Keyword(s):

Escherichia Coli ◽

Blot Hybridization ◽

Carbapenem Resistance ◽

Southern Blot Hybridization ◽

Control Measures ◽

Rrna Gene ◽

Limited Information ◽

E Coli ◽

Carbapenem Resistant ◽

Antimicrobial Resistance Genes

Abstract Background: Recently, the spread of NDM-5-producing Escherichia coli has become a severe challenge in clinical therapy, which necessitates reliable detection and surveillance methods. However, limited information is available regarding the prevalence and dissemination of the blaNDM-5 gene in Escherichia coli in China. Therefore, we investigated the dissemination of the blaNDM-5 gene in carbapenem-resistant Escherichia coli isolates from different regions in China.Methods: A total of 1,180 carbapenem-resistant enterobacteriaceae strains were obtained from patients admitted to the 20 sentinel hospitals in eight cities. Strains positive for blaNDM-5 were detected using the Vitek 2 compact system, 16S rRNA gene sequencing, PCR, the S1-pulsed-field gel electrophoresis assay, and Southern blot hybridization. The horizontal-transfer capability of the blaNDM gene was assessed by filter mating with a standard E. coli J53 azide-resistant strain as the recipient. Genotyping, susceptibility testing, and whole genome sequencing were performed. Results: Seven strains of blaNDM-5-positive E.coli was detected in 1180 clinical strains from different regions in China. The blaNDM-5-carrying strains showed resistance to multiple tested antibiotics and belonged to two widespread sequence types, ST167 and ST405. Antimicrobial resistance genes including blaCTX-M, blaOXA, blaCMY, and two novel blaTEM variants (blaTEM-230 and blaTEM-231) were also identified. Southern blotting located the blaNDM-5 gene on 46-kb IncX3 plasmids in all isolates, which showed only two single nucleotide differences between EJN003 and the other strains. Conclusions: This study further confirms the increasing occurrence of blaNDM-5-carrying IncX3 plasmids and the dissemination of carbapenem resistance in E. coli isolates via the plasmid from different parts in China, which warrants stringent surveillance and control measures.

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Molecular Epidemiology of Carbapenemases in Enterobacteriales from Humans, Animals, Food and the Environment

Antibiotics ◽

10.3390/antibiotics9100693 ◽

2020 ◽

Vol 9 (10) ◽

pp. 693

Author(s):

Gurleen Taggar ◽

Muhammad Attiq Rheman ◽

Patrick Boerlin ◽

Moussa Sory Diarra

Keyword(s):

Molecular Epidemiology ◽

Resistance Genes ◽

Control Strategies ◽

Companion Animals ◽

Hydrolytic Enzymes ◽

Carbapenem Resistance ◽

Carbapenem Resistant ◽

Class D ◽

Antimicrobial Resistance Genes ◽

Class B

The Enterobacteriales order consists of seven families including Enterobacteriaceae, Erwiniaceae, Pectobacteriaceae, Yersiniaceae, Hafniaceae, Morganellaceae, and Budviciaceae and 60 genera encompassing over 250 species. The Enterobacteriaceae is currently considered as the most taxonomically diverse among all seven recognized families. The emergence of carbapenem resistance (CR) in Enterobacteriaceae caused by hydrolytic enzymes called carbapenemases has become a major concern worldwide. Carbapenem-resistant Enterobacteriaceae (CRE) isolates have been reported not only in nosocomial and community-acquired pathogens but also in food-producing animals, companion animals, and the environment. The reported carbapenemases in Enterobacteriaceae from different sources belong to the Ambler class A (blaKPC), class B (blaIMP, blaVIM, blaNDM), and class D (blaOXA-48) β-lactamases. The carbapenem encoding genes are often located on plasmids or associated with various mobile genetic elements (MGEs) like transposons and integrons, which contribute significantly to their spread. These genes are most of the time associated with other antimicrobial resistance genes such as other β-lactamases, as well as aminoglycosides and fluoroquinolones resistance genes leading to multidrug resistance phenotypes. Control strategies to prevent infections due to CRE and their dissemination in human, animal and food have become necessary. Several factors involved in the emergence of CRE have been described. This review mainly focuses on the molecular epidemiology of carbapenemases in members of Enterobacteriaceae family from humans, animals, food and the environment.

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Carbapenem Resistance among Marine Bacteria—An Emerging Threat to the Global Health Sector

Microorganisms ◽

10.3390/microorganisms9102147 ◽

2021 ◽

Vol 9 (10) ◽

pp. 2147

Author(s):

Dewa A.P. Rasmika Dewi ◽

Torsten Thomas ◽

Ana Masara Ahmad Mokhtar ◽

Noreen Suliani Mat Nanyan ◽

Siti Balqis Zulfigar ◽

...

Keyword(s):

Health Sector ◽

Carbapenem Resistance ◽

Multidrug Resistant ◽

Pathogenic Microorganisms ◽

Global Public Health ◽

Marine Microbes ◽

Chronic Infections ◽

Genetic Transfer ◽

Healthcare Settings ◽

Carbapenem Resistant

The emergence of antibiotic resistance among pathogenic microorganisms is a major issue for global public health, as it results in acute or chronic infections, debilitating diseases, and mortality. Of particular concern is the rapid and common spread of carbapenem resistance in healthcare settings. Carbapenems are a class of critical antibiotics reserved for treatment against multidrug-resistant microorganisms, and resistance to this antibiotic may result in limited treatment against infections. In addition to in clinical facilities, carbapenem resistance has also been identified in aquatic niches, including marine environments. Various carbapenem-resistant genes (CRGs) have been detected in different marine settings, with the majority of the genes incorporated in mobile genetic elements, i.e., transposons or plasmids, which may contribute to efficient genetic transfer. This review highlights the potential of the marine environment as a reservoir for carbapenem resistance and provides a general overview of CRG transmission among marine microbes.

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Genomic background of a colistin-resistant and highly virulent MCR-1-positive Escherichia coli ST6395 from a broiler chicken in Pakistan

Pathogens and Disease ◽

10.1093/femspd/ftz064 ◽

2019 ◽

Vol 77 (7) ◽

Cited By ~ 1

Author(s):

Mashkoor Mohsin ◽

Mariya Azam ◽

Sajjad ur Rahman ◽

Fernanda Esposito ◽

Fábio P Sellera ◽

...

Keyword(s):

Public Health ◽

Escherichia Coli ◽

Galleria Mellonella ◽

Public Health Issue ◽

Infection Model ◽

Global Public Health ◽

Potential Threat ◽

In Vivo Experiments ◽

Antimicrobial Resistance Genes

ABSTRACT The convergence of high virulence and multidrug resistance (MDR) in Gram-negative pathogens circulating at the human–animal interface is a critical public health issue. We hereby report the genomic characteristics and virulent behavior of a colistin-resistant Escherichia coli, serotype ONT:H26, belonging to ST6395, isolated from a healthy broiler in Pakistan. This strain harbored multiple antimicrobial resistance genes, including mcr-1.1 and blaCARB-2, besides cma (colicin M) and astA [heat-stable enterotoxin 1 (EAST1) toxin] virulence genes. In vivo experiments carried out with the Galleria mellonella infection model revealed that MCR-1-positive E. coli ST6395 killed 96.4% of the larvae at 18 hour post-infection. Interplay between resistance and virulence in clinically important pathogens could be a potential threat, representing a serious challenge to global public health.

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Whole-Genome Sequencing Reveals Diversity of Carbapenem-Resistant Pseudomonas aeruginosa Collected Through the Emerging Infections Program

Infection Control and Hospital Epidemiology ◽

10.1017/ice.2020.1194 ◽

2020 ◽

Vol 41 (S1) ◽

pp. s513-s514

Author(s):

Richard Stanton ◽

Jonathan Daniels ◽

Erin Breaker ◽

Davina Campbell ◽

Joseph Lutgring ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

High Risk ◽

Efflux Pump ◽

Resistance Mutation ◽

Carbapenem Resistance ◽

Emerging Infections ◽

Carbapenem Resistant ◽

Antimicrobial Resistance Genes ◽

Chromosomal Mutations ◽

Sequence Types

Background: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a frequent cause of healthcare-associated infections (HAIs). The CDC Emerging Infections Program (EIP) conducted population and laboratory-based surveillance of CRPA in selected areas in 8 states from August 1, 2016, through July 31, 2018. We aimed to describe the molecular epidemiology and mechanisms of resistance of CRPA isolates collected through this surveillance. Methods: We defined a case as the first isolate of P. aeruginosa resistant to imipenem, meropenem, or doripenem from the lower respiratory tract, urine, wounds, or normally sterile sites identified from a resident of the EIP catchment area in a 30-day period; EIP sites submitted a systematic random sample of isolates to CDC for further characterization. Of 1,021 CRPA clinical isolates submitted, 707 have been sequenced to date using an Illumina MiSeq. Sequenced genomes were classified using the 7-gene multilocus sequence typing (MLST) scheme, and a core genome MLST (cgMLST) scheme was used to determine phylogeny. Antimicrobial resistance genes were identified using publicly available databases, and chromosomal mechanisms of carbapenem resistance were determined using previously validated genetic markers. Results: There were 189 sequence types (STs) among the 707 sequenced genomes (Fig. 1). The most frequently occurring were high-risk clones ST235 (8.5%) and ST298 (4.7%), which were found across all EIP sites. Carbapenemase genes were identified in 5 (<1%) isolates. Overall, 95.6% of the isolates had chromosomal mutations associated with carbapenem resistance: 93.2% had porinD-associated mutations that decrease membrane permeability to the drugs; 24.8% had mutations associated with overexpression of the multidrug efflux pump MexAB-OprM; and 22.9% had mutations associated with overexpression of the endogenous β-lactamase ampC. More than 1 such chromosomal resistance mutation type was present in 37.8% of the isolates. Conclusions: The diversity of the sequence types demonstrates that HAIs caused by CRPA can arise from a variety of strains and that high-risk clones are broadly disseminated across the EIP sites but are a minority of CRPA strains overall. Carbapenem resistance in P. aeruginosa was predominantly driven by chromosomal mutations rather than acquired mechanisms (ie, carbapenemases). The diversity of the CRPA isolates and the lack of carbapenemase genes suggest that this ubiquitous pathogen can readily evolve chromosomal resistance mechanisms, but unlike carbapenemases, these cannot be easily spread through horizontal transfer.Funding: NoneDisclosures: None

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Stool Samples of Acute Diarrhea Inpatients as a Reservoir of ST11 Hypervirulent KPC-2-Producing Klebsiella pneumoniae

mSystems ◽

10.1128/msystems.00498-20 ◽

2020 ◽

Vol 5 (3) ◽

Cited By ~ 4

Author(s):

Beiwen Zheng ◽

Hao Xu ◽

Tao Lv ◽

Lihua Guo ◽

Yu Xiao ◽

...

Keyword(s):

Public Health ◽

Klebsiella Pneumoniae ◽

Carbapenem Resistance ◽

Zhejiang Province ◽

Public Health Issue ◽

Resistant Bacteria ◽

Phylogenetic Tree Analysis ◽

Content Type ◽

Carbapenem Resistant ◽

Stool Samples

ABSTRACT The emergence and spread of carbapenem-resistant hypervirulent Klebsiella pneumoniae sequence type 11 (ST11-CR-HvKP) in China are a great concern in the public health community. However, the underlying mechanism that enables its wide dissemination in China remains unclear. Here, we investigated the prevalence of carriage of carbapenemase-producing Enterobacteriaceae (CPE) among inpatients with diarrhea in a teaching hospital over 1 year to identify ST11-CR-HvKP reservoirs and to understand the genetic background and plasmid profiles of these pathogens. As assessed by stool analysis, the CPE colonization rate (12.4%) among the inpatients with diarrhea was high (12.4%). Antibiotic exposure, surgical history, and CPE positivity were correlated. Genomic investigation of 65 carbapenem-resistant K. pneumoniae isolates indicated a shared bacterial population in various wards. According to maximum likelihood phylogenetic tree analysis, these isolates were partitioned into three major clades. Analysis of the wzi locus revealed three different K types (KL105, KL47, and K64) among the ST11 isolates, indicating the genetic diversity of these isolates. Genetic and sequence mapping revealed the complexity of virulence and resistance plasmid sets harbored by the isolates. These observations indicate that the dissemination of resistant bacteria is more complex than initially anticipated and possibly involves multiple K. pneumoniae ST11 lineages and a variety of virulence plasmids. Collectively, we show for the first time that stool may be a source of ST11-CR-HvKP isolates. Furthermore, the findings reveal the silent dissemination of ST11-CR-HvKP bacteria in Zhejiang Province, China. Future investigations are warranted to determine the association between rectal colonization by ST11-CR-HvKP and clinical infections. IMPORTANCE China has been experiencing a rapid increase in the number of nosocomial infections caused by carbapenem-resistant Klebsiella pneumoniae ST11 (ST11-CRKP) for decades. The emergence of hypervirulent ST11-CRKP (ST11-CR-HvKP) strains is expected to become a serious public health issue in China, considering that carbapenem resistance and virulence have converged in an epidemic clone. K. pneumoniae strains that colonize the human intestinal tract may become a reservoir of virulence and carbapenemase-encoding genes. Here, we first characterized the genotypes and antimicrobial phenotypes of ST11-CR-HvKP strains isolated from diarrheal stool samples of inpatients in Zhejiang Province, China. Active surveillance approaches based on the findings of the present study should be implemented, particularly in intensive care units, to combat the spread of ST11-CR-HvKP and to improve treatment.

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Virulence characterization and clonal analysis of uropathogenic Escherichia coli metallo-beta-lactamase-producing isolates

Annals of Clinical Microbiology and Antimicrobials ◽

10.1186/s12941-021-00457-4 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Fatemeh Zangane Matin ◽

Seyedeh Elham Rezatofighi ◽

Mohammad Roayaei Ardakani ◽

Mohammad Reza Akhoond ◽

Fahimeh Mahmoodi

Keyword(s):

Public Health ◽

Escherichia Coli ◽

Virulence Genes ◽

Antimicrobial Agents ◽

Carbapenem Resistance ◽

Cross Sectional Study ◽

Beta Lactamase ◽

Global Public Health ◽

Cross Sectional ◽

Carbapenem Resistant

Abstract Background Uropathogenic Escherichia coli (UPEC) is a major cause of urinary tract infection (UTI); however, treatment of UTI has been challenging due to increased antimicrobial resistance (AMR). One of the most important types of AMR is carbapenem resistance (CR). CR bacteria are known as an important threat to global public health today. Class B metallo-beta-lactamases (MBLs) are one of the major factors for resistance against carbapenems. We aimed to investigate the characteristics of UPEC isolates producing MBL. Methods A cross-sectional study was conducted from October 2018 to December 2019 in Ahvaz; Iran. UPEC isolates were identified by biochemical and molecular methods. Metallo-beta-lactamase-producing isolates were detected using modified carbapenem inactivation method (mCIM) and EDTA-CIM (eCIM) tests. MBL genes, phylogenetic group, and virulence genes profile of carbapenem resistant isolates were determined. Conjugation assay and plasmid profiling were conducted to evaluate the ability of transferring of CR to other E. coli isolates. Clonal similarity of isolates were assessed using Enterobacterial intergenic repetitive element sequence (ERIC)-PCR. Results Among 406 UPEC isolates, 12 (2.95%) carbapenem-resistant were detected of which 11 were phenotypically MBL-producing strains. Four isolates were resistant to all investigated antimicrobial agents and were considered possible pandrug-resistant (PDR). blaNDM, blaOXA-48, blaIMP-1, and blaIMP-2 genes were found in 9, 5, 1, and 1 isolates, respectively. Among 30 virulence genes investigated, the traT, fyuA followed by fimH, and iutA with the frequency of 8 (66.7%), 8 (66.7%), 7 (58.3%), and 7 (58.3%) were the most identified genes, respectively. Siderophore production was the main virulence trait among carbapenem-resistant UPEC isolates. Except for two, all other isolates showed weak to moderate virulence index. In all recovered isolates, CR was readily transmitted via plasmids to other isolates during conjugation experiments. Conclusion MBL and carbapenemase genes, especially blaNDM and blaOXA-48 are spreading rapidly among bacteria, which can be a threat to global public health. Therefore monitoring the emergence and dissemination of new AMR is necessary to continuously refine guidelines for empiric antimicrobial therapy. Understanding the mechanisms of resistance and virulence in this group of bacteria can play an effective role in providing new therapeutic methods.

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Stress-Adaptive Responses Associated with High-Level Carbapenem Resistance in KPC-ProducingKlebsiella pneumoniae

Journal of Pathogens ◽

10.1155/2018/3028290 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Sheila Adams-Sapper ◽

Adam Gayoso ◽

Lee. W. Riley

Keyword(s):

Carbapenem Resistance ◽

Protein Translation ◽

Global Public Health ◽

Human Pathogens ◽

Adaptive Responses ◽

Carbapenem Resistant ◽

Expression Of Genes ◽

Different Strains ◽

High Level

Carbapenem-resistant Enterobacteriaceae (CRE) organisms have emerged to become a major global public health threat among antimicrobial resistant bacterial human pathogens. Little is known about how CREs emerge. One characteristic phenotype of CREs is heteroresistance, which is clinically associated with treatment failure in patients given a carbapenem. Throughin vitrowhole-transcriptome analysis we tracked gene expression over time in two different strains (BR7, BR21) of heteroresistant KPC-producingKlebsiella pneumoniae,first exposed to a bactericidal concentration of imipenem followed by growth in drug-free medium. In both strains, the immediate response was dominated by a shift in expression of genes involved in glycolysis toward those involved in catabolic pathways. This response was followed by global dampening of transcriptional changes involving protein translation, folding and transport, and decreased expression of genes encoding critical junctures of lipopolysaccharide biosynthesis. The emerged high-level carbapenem-resistant BR21 subpopulation had a prophage (IS1) disruptingompK36associated with irreversible OmpK36 porin loss. On the other hand, OmpK36 loss in BR7 was reversible. The acquisition of high-level carbapenem resistance by the two heteroresistant strains was associated with distinct and shared stepwise transcriptional programs. Carbapenem heteroresistance may emerge from the most adaptive subpopulation among a population of cells undergoing a complex set of stress-adaptive responses.

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