Insertion sequences disrupting mgrB in carbapenem-resistant Klebsiella pneumoniae strains in Brazil

Silva, Daniely Martins da; Faria-Junior, Célio; Nery, Danielly R.; Oliveira, Pâmela Maria de; Silva, Lilian de Oliveira Rodrigues; Alves, Everton Giovanni; Lima, Glaura Regina de Castro e Caldo; Pereira, Alex Leite

doi:10.1016/j.jgar.2020.11.003

Cited by 19 publications

(13 citation statements)

References 36 publications

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“…However, K. pneumoniae isolates that are resistant to both polymyxin and carbapenem have been documented, and the underlying mechanism was under surveillance ( 10 , 16 , 17 ). Predominant molecular characteristics of PR-CRKP strains may differ geographically and over time ( 10 , 16 , 18 , 19 ). Therefore, in the study, the genomic survey of clinical PR-CRKP was conducted to investigate the genetic alterations in these isolates circulating in China.…”

Section: Discussionmentioning

confidence: 99%

Genetic Diversity of Polymyxin-Resistance Mechanisms in Clinical Isolates of Carbapenem-Resistant Klebsiella pneumoniae: a Multicenter Study in China

Liu

Lei

et al. 2023

Microbiol Spectr

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Section: Discussionmentioning

confidence: 99%

Genetic Diversity of Polymyxin-Resistance Mechanisms in Clinical Isolates of Carbapenem-Resistant Klebsiella pneumoniae: a Multicenter Study in China

Liu

Lei

et al. 2023

Microbiol Spectr

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“…A 100% identity match between the ISKpn25 found on plasmids and the ISKpn25 disrupting the chromosomal mgrB gene has been reported across two K. pneumoniae STs: ST258, and ST512 in strains carrying both pKpQil‐like plasmids and a disrupted chromosomal mgrB gene across independent investigation of colistin resistant K. pneumoniae (Cienfuegos‐Gallet et al, 2017; Giordano et al, 2018). ISKpn26 and IS903B have been found inserted into the mgrB gene of K. pneumoniae (Nirwan et al, 2021; Silva et al, 2021). These IS share high identity to their respective reference IS elements identified on plasmids.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of insertion sequence elements in plasmids relating to mgrB gene disruption causing colistin resistance in Klebsiella pneumoniae

2022

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Colistin is a last resort antibiotic for the treatment of carbapenemase producing Klebsiella pneumoniae. The disruption of the mgrB gene by insertion sequences (ISs) is a mechanism mediating colistin resistance. Plasmids encode mobilizable IS elements which integrate into the mgrB gene in K. pneumoniae causing gene inactivation and colistin resistance. The species prevalence of mgrB-gene disrupting insertion elements ISL3 (ISKpn25), IS5 (ISKpn26), ISKpn14, and IS903B present on plasmids were assessed. IS containing plasmids were also scanned for antimicrobial resistance genes, including carbapenem resistant genes.Plasmids encoding ISs are abundant in K. pneumoniae. IS903B was found in 28 unique Inc groups, while ISKpn25 was largely carried by IncFIB(pQil) plasmids.ISKpn26 and ISKpn14 were most often found associated with IncFII(pHN7A8) plasmids. Of the 34 unique countries which contained any of the IS elements, ISKpn25 was identified from 26. ISKpn26, ISKpn14, and IS903B ISs were identified from 89.3%, 44.9%, and 23.9% plasmid samples from China. Plasmids carrying ISKpn25, ISKpn14, and ISKpn26 IS have a 4.6-, 6.0-, and 6.6-fold higher carbapenemase gene count, respectively, relative to IS903B-carrying plasmids. IS903B bearing plasmids have a 20-, 5-, and 5-fold higher environmental source isolation count relative to ISKpn25, ISKpn14, and ISKpn26 bearing plasmids. ISKpn25 present on IncFIB(pQil) sourced from clinical settings is established across multiple countries, while ISKpn26, ISKpn14, and IS903B appear most often in China. Carbapenemase presence in tandem with IS elements may help promote an extensively drug resistant profile in K. pneumoniae limiting already narrow treatment options.

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“…Mounting evidence in recent years has thrown light on its role in resistance to antibiotics, particularly antimicrobial peptides such as polymyxins ( Mmatli et al, 2020 ). The clinical relevance of these findings was brought to the fore when a number of studies identified inactivating mutations in mgrB in carbapenem/colistin-resistant Klebsiella pneumoniae ( Cannatelli et al, 2013 ; Haeili et al, 2017 ; Silva et al, 2021 ). Derepression of PhoPQ in Klebsiella results in alterations in the structure of Lipid A, conferring resistance to colistin ( Kidd et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Adaptation and compensation in a bacterial gene regulatory network evolving under antibiotic selection

Patel

Matange

2021

eLife

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Gene regulatory networks allow organisms to generate coordinated responses to environmental challenges. In bacteria, regulatory networks are re-wired and re-purposed during evolution, though the relationship between selection pressures and evolutionary change is poorly understood. In this study, we discover that the early evolutionary response of Escherichia coli to the antibiotic trimethoprim involves derepression of PhoPQ signaling, an Mg2+-sensitive two-component system, by inactivation of the MgrB feedback-regulatory protein. We report that derepression of PhoPQ confers trimethoprim-tolerance to E. coli by hitherto unrecognized transcriptional upregulation of dihydrofolate reductase (DHFR), target of trimethoprim. As a result, mutations in mgrB precede and facilitate the evolution of drug resistance. Using laboratory evolution, genome sequencing, and mutation re-construction, we show that populations of E. coli challenged with trimethoprim are faced with the evolutionary ‘choice’ of transitioning from tolerant to resistant by mutations in DHFR, or compensating for the fitness costs of PhoPQ derepression by inactivating the RpoS sigma factor, itself a PhoPQ-target. Outcomes at this evolutionary branch-point are determined by the strength of antibiotic selection, such that high pressures favor resistance, while low pressures favor cost compensation. Our results relate evolutionary changes in bacterial gene regulatory networks to strength of selection and provide mechanistic evidence to substantiate this link.

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Insertion sequences disrupting mgrB in carbapenem-resistant Klebsiella pneumoniae strains in Brazil

Cited by 19 publications

References 36 publications

Genetic Diversity of Polymyxin-Resistance Mechanisms in Clinical Isolates of Carbapenem-Resistant Klebsiella pneumoniae: a Multicenter Study in China

Genetic Diversity of Polymyxin-Resistance Mechanisms in Clinical Isolates of Carbapenem-Resistant Klebsiella pneumoniae: a Multicenter Study in China

Prevalence of insertion sequence elements in plasmids relating to mgrB gene disruption causing colistin resistance in Klebsiella pneumoniae

Adaptation and compensation in a bacterial gene regulatory network evolving under antibiotic selection

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