scholarly journals Genetic determinants facilitating the evolution of resistance to carbapenem antibiotics

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Peijun Ma ◽  
Lorrie L He ◽  
Alejandro Pironti ◽  
Hannah H Laibinis ◽  
Christoph M Ernst ◽  
...  
Keyword(s):  
Clinical Isolate ◽  
Insertional Mutagenesis ◽  
Carbapenem Resistance ◽  
Genetic Determinants ◽  
Stepping Stones ◽  
Resistant Species ◽  
Carbapenem Resistant ◽  
Evolution Of Resistance ◽  
High Level ◽  
Level Resistance

In this era of rising antibiotic resistance, in contrast to our increasing understanding of mechanisms that cause resistance, our understanding of mechanisms that influence the propensity to evolve resistance remains limited. Here, we identified genetic factors that facilitate the evolution of resistance to carbapenems, the antibiotic of 'last resort,' in Klebsiella pneumoniae, the major carbapenem resistant species. In clinical isolates, we found that high-level transposon insertional mutagenesis plays an important role in contributing to high-level resistance frequencies in several major and emerging carbapenem-resistant lineages. A broader spectrum of resistance-conferring mutations for select carbapenems such as ertapenem also enables higher resistance frequencies and importantly, creates stepping-stones to achieve high-level resistance to all carbapenems. These mutational mechanisms can contribute to the evolution of resistance, in conjunction with the loss of systems that restrict horizontal resistance gene uptake, such as the CRISPR-Cas system. Given the need for greater antibiotic stewardship, these findings argue that in addition to considering the current efficacy of an antibiotic for a clinical isolate in antibiotic selection, considerations of future efficacy are also important. The genetic background of a clinical isolate and the exact antibiotic identity can and should also be considered as it is a determinant of a strain's propensity to become resistant. Together, these findings thus provide a molecular framework for understanding acquisition of carbapenem resistance in K. pneumoniae with important implications for diagnosing and treating this important class of pathogens.

scholarly journals Genetic determinants facilitating the evolution of resistance to carbapenem antibiotics

2021 ◽  
Author(s):  
Peijun Ma ◽  
Lorrie L. He ◽  
Alejandro Pironti ◽  
Hannah H. Laibinis ◽  
Christoph M. Ernst ◽  
...  
Keyword(s):  
Clinical Isolate ◽  
Insertional Mutagenesis ◽  
Carbapenem Resistance ◽  
Genetic Determinants ◽  
Stepping Stones ◽  
Resistant Species ◽  
Carbapenem Resistant ◽  
Evolution Of Resistance ◽  
High Level ◽  
Level Resistance

AbstractIn this era of rising antibiotic resistance, in contrast to our increasing understanding of mechanisms that cause resistance, our understanding of mechanisms that influence the propensity to evolve resistance remains limited. Here, we identified genetic factors that facilitate the evolution of resistance to carbapenems, the antibiotic of “last resort,” inKlebsiella pneumoniae, the major carbapenem resistant species. In clinical isolates, we found that high-level transposon insertional mutagenesis plays an important role in contributing to high-level resistance frequencies in several major and emerging carbapenem-resistant lineages. A broader spectrum of resistance-conferring mutations for select carbapenems such as ertapenem also enables higher resistance frequencies and importantly, creates stepping-stones to achieve high-level resistance to all carbapenems. These mutational mechanisms can contribute to the evolution of resistance, in conjunction with the loss of systems that restrict horizontal resistance gene uptake, such as the CRISPR-Cas system. Given the need for greater antibiotic stewardship, these findings argue that in addition to considering the current efficacy of an antibiotic for a clinical isolate in antibiotic selection, considerations of future efficacy are also important. The genetic background of a clinical isolate and the exact antibiotic identity can and should also be considered as it is a determinant of a strain’s propensity to become resistant. Together, these findings thus provide a molecular framework for understanding acquisition of carbapenem resistance inK. pneumoniaewith important implications for diagnosing and treating this important class of pathogens.

scholarly journals Molecular pathways to high-level azithromycin resistance in Neisseria gonorrhoeae

2021 ◽  
Author(s):  
J G E Laumen ◽  
S S Manoharan-Basil ◽  
E Verhoeven ◽  
S Abdellati ◽  
I De Baetselier ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Ribosomal Proteins ◽  
Efflux Pump ◽  
23S Rrna ◽  
Rrna Gene ◽  
23S Rrna Gene ◽  
Evolution Of Resistance ◽  
High Level ◽  
Azithromycin Resistance ◽  
Level Resistance

Abstract Background The prevalence of azithromycin resistance in Neisseria gonorrhoeae is increasing in numerous populations worldwide. Objectives To characterize the genetic pathways leading to high-level azithromycin resistance. Methods A customized morbidostat was used to subject two N. gonorrhoeae reference strains (WHO-F and WHO-X) to dynamically sustained azithromycin pressure. We tracked stepwise evolution of resistance by whole genome sequencing. Results Within 26 days, all cultures evolved high-level azithromycin resistance. Typically, the first step towards resistance was found in transitory mutations in genes rplD, rplV and rpmH (encoding the ribosomal proteins L4, L22 and L34 respectively), followed by mutations in the MtrCDE-encoded efflux pump and the 23S rRNA gene. Low- to high-level resistance was associated with mutations in the ribosomal proteins and MtrCDE efflux pump. However, high-level resistance was consistently associated with mutations in the 23S ribosomal RNA, mainly the well-known A2059G and C2611T mutations, but also at position A2058G. Conclusions This study enabled us to track previously reported mutations and identify novel mutations in ribosomal proteins (L4, L22 and L34) that may play a role in the genesis of azithromycin resistance in N. gonorrhoeae.

scholarly journals High-Level Carbapenem Resistance in OXA-232-Producing Raoultella ornithinolytica Triggered by Ertapenem Therapy

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
Alina Iovleva ◽  
Roberta T. Mettus ◽  
Christi L. McElheny ◽  
Marissa P. Griffith ◽  
Mustapha M. Mustapha ◽  
...  
Keyword(s):  
Rapid Development ◽  
Carbapenem Resistance ◽  
Resistant Isolate ◽  
Clinical Microbiology Laboratory ◽  
Loss Of Function ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Class D ◽  
Fold Reduction ◽  
High Level

ABSTRACT OXA-232 is an OXA-48-group class D β-lactamase that hydrolyzes expanded-spectrum cephalosporins and carbapenems at low levels. Clinical strains producing OXA-232 are sometimes susceptible to carbapenems, making it difficult to identify them in the clinical microbiology laboratory. We describe the development of carbapenem resistance in sequential clinical isolates of Raoultella ornithinolytica carrying blaOXA-232 in a hospitalized patient, where the ertapenem MIC increased from 0.5 μg/ml to 512 μg/ml and the meropenem MIC increased from 0.125 μg/ml to 32 μg/ml during the course of ertapenem therapy. Whole-genome sequencing (WGS) analysis identified loss-of-function mutations in ompC and ompF in carbapenem-resistant isolates that were not present in the initial carbapenem-susceptible isolate. Complementation of a carbapenem-resistant isolate with an intact ompF gene resulted in 16- to 32-fold reductions in carbapenem MICs, whereas complementation with intact ompC resulted in a 2-fold reduction in carbapenem MICs. Additionally, blaOXA-232 expression increased 2.9-fold in a carbapenem-resistant isolate. Rapid development of high-level carbapenem resistance in initially carbapenem-susceptible OXA-232-producing R. ornithinolytica under selective pressure from carbapenem therapy highlights the diagnostic challenges in detecting Enterobacteriaceae strains producing this inefficient carbapenemase.

scholarly journals Multicity Outbreak of Carbapenem-Resistant Acinetobacter baumannii Isolates Producing the Carbapenemase OXA-40

2006 ◽  
Vol 50 (9) ◽  
pp. 2941-2945 ◽  
Author(s):  
Karen Lolans ◽  
Thomas W. Rice ◽  
L. Silvia Munoz-Price ◽  
John P. Quinn
Keyword(s):  
Acinetobacter Baumannii ◽  
Carbapenem Resistance ◽  
The United States ◽  
Nucleotide Sequencing ◽  
Sequencing Analysis ◽  
Carbapenem Resistant ◽  
Extended Care ◽  
Care Facilities ◽  
High Level ◽  
First Time

ABSTRACT During 2005 we detected a multicity outbreak of infections or colonization due to high-level imipenem-resistant Acinetobacter baumannii (MIC, 64 μg/ml). One hundred isolates from diverse sources were obtained from seven acute-care hospitals and two extended-care facilities; 97% of the isolates belonged to one clone. Susceptibility testing of the first 42 isolates (January to April 2005) revealed broad resistance profiles. Half of the isolates were susceptible to ceftazidime, with many isolates susceptible only to colistin. The level of AmpC β-lactamase expression was stronger in isolates resistant to ceftazidime. PCR and subsequent nucleotide sequencing analysis identified bla OXA-40. The presence of an OXA-40 β-lactamase in these isolates correlated with the carbapenem resistance. By Southern blot analysis, a bla OXA-40-specific probe revealed that the gene was both plasmid and chromosomally located. This is the first time in the United States that such carbapenem resistance in A. baumannii has been attributable to a carbapenemase.

scholarly journals Extended-Spectrum Cephalosporinase in Acinetobacter baumannii

2010 ◽  
Vol 54 (8) ◽  
pp. 3484-3488 ◽  
Author(s):  
José-Manuel Rodríguez-Martínez ◽  
Patrice Nordmann ◽  
Esthel Ronco ◽  
Laurent Poirel
Keyword(s):  
Acinetobacter Baumannii ◽  
Clinical Isolate ◽  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Extended Spectrum ◽  
Class C ◽  
High Level ◽  
Level Resistance

ABSTRACT An AmpC-type β-lactamase conferring high-level resistance to expanded-spectrum cephalosporins and monobactams was characterized from an Acinetobacter baumannii clinical isolate. This class C β-lactamase (named ADC-33) possessed a Pro210Arg substitution together with a duplication of an Ala residue at position 215 (inside the Ω-loop) compared to a reference AmpC cephalosporinase from A. baumannii. ADC-33 hydrolyzed ceftazidime, cefepime, and aztreonam at high levels, which allows the classification of this enzyme as an extended-spectrum AmpC (ESAC). Site-directed mutagenesis confirmed the role of both substitutions in its ESAC property.

scholarly journals Association of two resistance mechanisms in a clinical isolate of Enterobacter cloacae with high-level resistance to imipenem.

1991 ◽  
Vol 35 (6) ◽  
pp. 1093-1098 ◽  
Author(s):  
E H Lee ◽  
M H Nicolas ◽  
M D Kitzis ◽  
G Pialoux ◽  
E Collatz ◽  
...  
Keyword(s):  
Clinical Isolate ◽  
Enterobacter Cloacae ◽  
Resistance Mechanisms ◽  
High Level ◽  
Level Resistance

scholarly journals Outbreak Caused by NDM-1- and RmtB-Producing Escherichia coli in Bulgaria

2014 ◽  
Vol 58 (4) ◽  
pp. 2472-2474 ◽  
Author(s):  
Laurent Poirel ◽  
Encho Savov ◽  
Arzu Nazli ◽  
Angelina Trifonova ◽  
Iva Todorova ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
16S Rrna ◽  
Sequence Type ◽  
Content Type ◽  
E Coli ◽  
Carbapenem Resistant ◽  
The World ◽  
High Level ◽  
16S Rrna Methylase ◽  
Level Resistance

ABSTRACTTwelve consecutive carbapenem-resistantEscherichia coliisolates were recovered from patients (infection or colonization) hospitalized between March and September 2012 in different units at a hospital in Bulgaria. They all produced the carbapenemase NDM-1 and the extended-spectrum-β-lactamase CTX-M-15, together with the 16S rRNA methylase RmtB, conferring high-level resistance to all aminoglycosides. All those isolates were clonally related and belonged to the same sequence type, ST101. In addition to being the first to identify NDM-producing isolates in Bulgaria, this is the very first study reporting an outbreak of NDM-1-producingE. coliin the world.

scholarly journals Carbapenem-Resistant Pseudomonas aeruginosa in Malaysia Producing IMP-7 β-Lactamase

2002 ◽  
Vol 46 (10) ◽  
pp. 3286-3287 ◽  
Author(s):  
Siaw Eng Ho ◽  
Geetha Subramaniam ◽  
Selvi Palasubramaniam ◽  
Parasakthi Navaratnam
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Dna Sequencing ◽  
Isoelectric Focusing ◽  
Carbapenem Resistant ◽  
High Level ◽  
Level Resistance

ABSTRACT We have isolated and identified a carbapenem-resistant Pseudomonas aeruginosa strain from Malaysia that produces an IMP-7 metallo-β-lactamase. This isolate showed high-level resistance to meropenem and imipenem, the MICs of which were 256 and 128 μg/ml, respectively. Isoelectric focusing analyses revealed pI values of >9.0, 8.2, and 7.8, which indicated the possible presence of IMP and OXA. DNA sequencing confirmed the identity of the IMP-7 determinant.

scholarly journals A pneumococcal clinical isolate with high-level resistance to cefotaxime and ceftriaxone.

1992 ◽  
Vol 36 (4) ◽  
pp. 886-889 ◽  
Author(s):  
A M Figueiredo ◽  
J D Connor ◽  
A Severin ◽  
M V Vaz Pato ◽  
A Tomasz
Keyword(s):  
Clinical Isolate ◽  
High Level ◽  
Level Resistance
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