Artificial Activation of Escherichia coli mazEF and hipBA Toxin–Antitoxin Systems by Antisense Peptide Nucleic Acids as an Antibacterial Strategy

Równicki, Marcin; Pieńko, Tomasz; Czarnecki, Jakub; Kolanowska, Monika; Bartosik, Dariusz; Trylska, Joanna

doi:10.3389/fmicb.2018.02870

Cited by 31 publications

(31 citation statements)

References 98 publications

(120 reference statements)

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“…Furthermore, since mazEF and hipBA toxin-antitoxin systems were detected, these isolates are bound to the plasmid, and losing the plasmid will trigger the pathway of cellular death (Engelberg-Kulka et al, 2005). Strategies to target these systems appear to be a promising therapy to defeat these MDR pathogens due to the bactericidal effect (Rownicki et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

mcr-Colistin Resistance Genes Mobilized by IncX4, IncHI2, and IncI2 Plasmids in Escherichia coli of Pigs and White Stork in Spain

et al. 2020

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Colistin has become the last-line antimicrobial for the treatment of multidrug resistant (MDR) Enterobacterales in human medicine. To date, several colistin resistance genes have been described. Of them mcr-1 is disseminated worldwide in Escherichia coli of human and animal origin. The aim of this study was to characterize mcr-mediated resistance plasmids from E. coli of animal origin in Spain. From our strain collection, 70 E. coli of pig origin collected between 2005 and 2014 (10 per year, except for years 2009-2010-2013) were randomly selected and screened for the presence of mcr-genes. Additionally, 20 E. coli isolated in 2011 from white storks (Ciconia ciconia) from the same urban household waste landfill associated colony were also included. Whole genome sequencing of mcr-positive isolates was carried out on a MiSeq (Illumina). Hybrid whole genome sequencing strategy combining nanopore and Illumina technologies were performed in a selection of isolates to close the genomes and plasmids and identify the presence of antimicrobial resistance genes. Minimum inhibitory concentration (MIC) was used to assess the susceptibility to colistin. Mating experiments were carried out to evaluate transferability of the mcr-genes. A total of 19 mcr-1 and one mcr-4 positive isolates were detected, 15 from pigs distributed during the study period, and five from storks collected in 2011. No other mcr-variants were found. The MICs for colistin ranged between 4 and >4 mg/L. High diversity of STs were detected among the mcr-1 positive E. coli isolates, with only ST-10 shared between pigs and white storks. Except for one isolate, all were genotypic and phenotypically MDR, and five of them also harbored cephalosporin resistance genes (bla CTX−M−14 , bla SHV−12 , and three bla CMY−2). mcr-1 genes were mobilizable by conjugation, associated with IncX4, IncHI2, and IncI2 plasmids. In our study, mcr-1 genes have been circulating in pig farms since 2005 harbored by a variety of E. coli clones. Its persistence may be driven by co-selection since plasmids containing mcr-1 also exhibit resistance to

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Section: Discussionmentioning

confidence: 99%

mcr-Colistin Resistance Genes Mobilized by IncX4, IncHI2, and IncI2 Plasmids in Escherichia coli of Pigs and White Stork in Spain

et al. 2020

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“…Therefore, inhibition of antitoxin translation should not influence the translation of the toxin protein. This strategy was tested by Równicki and co-workers who designed a peptide nucleic acid (PNA)-based treatment to inhibit translation of the antitoxins of the mazEF and hipBA TA systems of E. coli [63].…”

Section: Inhibition Of Antitoxin Translationmentioning

confidence: 99%

“…The sequence-specific antisense PNAs targeted either mazE or hipB antitoxin mRNAs and as a result lowered the cellular levels of these transcripts, which caused an effective inhibition of E. coli growth [63]. Importantly, the PNA treatment did not change the relative levels of the mazF or hipA A similar approach was applied in the case of two related TA systems-pemIK and moxXT of Bacillus anthracis.…”

Section: Inhibition Of Antitoxin Translationmentioning

confidence: 99%

“…Another PNA-based strategy, described in the same report, used PNA oligomers directed at the cellular target of the toxin, thus bypassing the involvement of the TA system. It was demonstrated that PNAs can mimic the action of the HipA toxin by silencing the gltX gene encoding its cellular target, glutamyl-tRNA synthase [63]. For these experiments, the PNA oligomers were conjugated with a cell penetrating peptide-(KFF) 3 K, which indicated the importance of employing an efficient carrier to introduce these antisense oligonucleotides into bacterial cells [63].…”

Section: Inhibition Of Antitoxin Translationmentioning

confidence: 99%

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Targeting Type II Toxin–Antitoxin Systems as Antibacterial Strategies

Równicki

Lasek

Trylska

et al. 2020

Toxins

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The identification of novel targets for antimicrobial agents is crucial for combating infectious diseases caused by evolving bacterial pathogens. Components of bacterial toxin–antitoxin (TA) systems have been recognized as promising therapeutic targets. These widespread genetic modules are usually composed of two genes that encode a toxic protein targeting an essential cellular process and an antitoxin that counteracts the activity of the toxin. Uncontrolled toxin expression may elicit a bactericidal effect, so they may be considered “intracellular molecular bombs” that can lead to elimination of their host cells. Based on the molecular nature of antitoxins and their mode of interaction with toxins, TA systems have been classified into six groups. The most prevalent are type II TA systems. Due to their ubiquity among clinical isolates of pathogenic bacteria and the essential processes targeted, they are promising candidates for the development of novel antimicrobial strategies. In this review, we describe the distribution of type II TA systems in clinically relevant human pathogens, examine how these systems could be developed as the targets for novel antibacterials, and discuss possible undesirable effects of such therapeutic intervention, such as the induction of persister cells, biofilm formation and toxicity to eukaryotic cells.

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“…Of note, inhibition of the anti-toxin component (such as DarG), either by the administration of selective inhibitors or by silencing (i.e. by sequence-specific antisense agents), could be envisaged as a novel therapeutic strategy [297].…”

Section: Conclusion: Targeting Toxin Adp-ribosyl Transferase Activitymentioning

confidence: 99%

Targeting ADP-ribosylation as an antimicrobial strategy

Catara

Corteggio

Valente

et al. 2019

Biochemical Pharmacology

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A B S T R A C T ADP-ribosylation (ADPr) is an ancient reversible modification of cellular macromolecules controlling major biological processes as diverse as DNA damage repair, transcriptional regulation, intracellular transport, immune and stress responses, cell survival and proliferation. Furthermore, enzymatic reactions of ADPr are central in the pathogenesis of many human diseases, including infectious conditions. By providing a review of ADPr signalling in bacterial systems, we highlight the relevance of this chemical modification in the pathogenesis of human diseases depending on host-pathogen interactions. The post-antibiotic era has raised the need to find alternative approaches to antibiotic administration, as major pathogens becoming resistant to antibiotics. An in-depth understanding of ADPr reactions provides the rationale for designing novel antimicrobial strategies for treatment of infectious diseases. In addition, the understanding of mechanisms of ADPr by bacterial virulence factors offers important hints to improve our knowledge on cellular processes regulated by eukaryotic homologous enzymes, which are often involved in the pathogenesis of human diseases.T large number of worldwide spread diseases, affecting humans, insects and plants [31,[56][57][58], with a great impact on human health. In addition, infectious diseases strongly affect the world economy in terms of costs for the human health as well as food and agricultural economic losses [59]. The use of antibiotics to counteract the pathogen infections has represented the therapeutic strategy of choice in the last century, however the emergence of antibiotic resistance strains represents the major challenge of the 21st century [60][61][62]. Targeting bacterial pathogenic mechanisms by disarming pathogens of virulence factors, for instance by inhibiting the enzymatic activity of bART, represents a valid alternative intervention strategy to overcome antibiotic resistance [63][64][65][66]. In addition, because of the conservation of ADPr systems throughout the evolution, the understanding of bacterial pathogenic mechanisms may contribute to unveil novel and conserved cellular processes regulated by ADPr in high organisms [34,45,67,68]. The dysregulation of such processes can be either cause of human diseases or be target of therapeutic intervention [39,[69][70][71].Herein, we will provide a summary of bacterial ADPr systems describing their pathogenic mechanisms and highlighting the similarities with ADPr systems in mammals as well. Further, we discuss the potential of targeting ADPr for therapeutic strategies of infection diseases. ADP-ribosylation in pathophysiologyADPr was originally described in the 60s; two independent studies reported the identification of a new polymer, poly(ADP-ribose) (PAR) synthesised from NAD + in vertebrate cells [72] and, simultaneously, the finding that bacterial DTX activity from C. diphteriae is dependent on NAD + content [73]. In the following decades, research in the field has expanded the involvement of ADPr ...

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Artificial Activation of Escherichia coli mazEF and hipBA Toxin–Antitoxin Systems by Antisense Peptide Nucleic Acids as an Antibacterial Strategy

Cited by 31 publications

References 98 publications

mcr-Colistin Resistance Genes Mobilized by IncX4, IncHI2, and IncI2 Plasmids in Escherichia coli of Pigs and White Stork in Spain

mcr-Colistin Resistance Genes Mobilized by IncX4, IncHI2, and IncI2 Plasmids in Escherichia coli of Pigs and White Stork in Spain

Targeting Type II Toxin–Antitoxin Systems as Antibacterial Strategies

Targeting ADP-ribosylation as an antimicrobial strategy

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