Prediction of Type II Toxin-Antitoxin Loci in Klebsiella pneumoniae Genome Sequences

Wei, Yiqing; Bi, Dexi; Wei, Dong‐Qing; Ou, Hong‐Yu

doi:10.1007/s12539-015-0135-6

Cited by 22 publications

(21 citation statements)

References 22 publications

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“…Some RelBE-like TA systems were also distributed in a manner different from that for the K. pneumoniae RelBE systems (59). Thus, the distributions of RelBE_1kp and RelBE_2kp loci differ in plasmids and chromosomes, although they were found in the same K. pneumoniae isolate (16,373). However, a detailed distribution and the implications for the development of a persistence phenotype in K. pneumoniae are unknown (373).…”

Section: Toxin-antitoxin Systemsmentioning

confidence: 97%

“…Klebsiella pneumoniae isolates have a major role in antibiotic resistance, and the genes for several type I and II TA systems (Hok/Sok, PemK/PemI, and CcdA/CccB) (16) have previously been identified on resistance plasmids carried by this bacterium (372). A bioinformatics approach was used to analyze the distribution of the locus of the type II system and to determine the variability in the TA loci from 10 complete sequenced genomes of K. pneumoniae, revealing numerous putative type II TA loci (373). Some RelBE-like TA systems were also distributed in a manner different from that for the K. pneumoniae RelBE systems (59).…”

Section: Toxin-antitoxin Systemsmentioning

confidence: 99%

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Mechanisms of Bacterial Tolerance and Persistence in the Gastrointestinal and Respiratory Environments

et al. 2018

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SUMMARYPathogens that infect the gastrointestinal and respiratory tracts are subjected to intense pressure due to the environmental conditions of the surroundings. This pressure has led to the development of mechanisms of bacterial tolerance or persistence which enable microorganisms to survive in these locations. In this review, we analyze the general stress response (RpoS mediated), reactive oxygen species (ROS) tolerance, energy metabolism, drug efflux pumps, SOS response, quorum sensing (QS) bacterial communication, (p)ppGpp signaling, and toxin-antitoxin (TA) systems of pathogens, such as , spp., spp., spp., , spp., spp., spp., and , all of which inhabit the gastrointestinal tract. The following respiratory tract pathogens are also considered:, ,, , and Knowledge of the molecular mechanisms regulating the bacterial tolerance and persistence phenotypes is essential in the fight against multiresistant pathogens, as it will enable the identification of new targets for developing innovative anti-infective treatments.

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Section: Toxin-antitoxin Systemsmentioning

confidence: 97%

Section: Toxin-antitoxin Systemsmentioning

confidence: 99%

Mechanisms of Bacterial Tolerance and Persistence in the Gastrointestinal and Respiratory Environments

et al. 2018

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“…K. pneumoniae devises various strategies to adapt to the action of various antimicrobial compounds, including TA system regulation (Navon-Venezia et al, 2017). In our previous in silico work, 212 putative type II TA loci were identified in 30 replicons of completely sequenced K. pneumoniae strains (Wei et al, 2015). Notably, the toxins containing the GNAT domain were prevalent.…”

Section: Introductionmentioning

confidence: 98%

Identification and characterization of acetyltransferase‐type toxin‐antitoxin locus in Klebsiella pneumoniae

Qian

Yao

Tai

et al. 2018

Molecular Microbiology

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A type II toxin-antitoxin (TA) system, in which the toxin contains a Gcn5-related N-acetyltransferase (GNAT) domain, has been characterized recently. GNAT toxin acetylates aminoacyl-tRNA and blocks protein translation. It is abolished by the cognate antitoxin that contains the ribbon-helix-helix (RHH) domain. Here, we present an experimental demonstration of the interaction of the GNAT-RHH complex with TA promoter DNA. First, the GNAT-RHH TA locus kacAT was found in Klebsiella pneumoniae HS11286, a strain resistant to multiple antibiotics. Overexpression of KacT halted cell growth and resulted in persister cell formation. The crystal structure also indicated that KacT is a typical acetyltransferase toxin. Co-expression of KacA neutralized KacT toxicity. Expression of the bicistronic kacAT locus was up-regulated during antibiotic stress. Finally, KacT and KacA formed a heterohexamer that interacted with promoter DNA, resulting in negative autoregulation of kacAT transcription. The N-terminus region of KacA accounted for specific binding to the palindromic sequence on the operator DNA, whereas its C-terminus region was essential for the inactivation of the GNAT toxin. These results provide an important insight into the regulation of the GNAT-RHH family TA system.

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“…Through subsequent validation, we have found that the organisation of SAS genes into bicistronic architectures along with a downstream -or in one case upstream -gene is a strong indicator of toxicity. Identification of bicistronic architectures has been used as a starting point for prediction of TAs previously (44,45). However, these studies have focussed on species that do not encode toxSASs, and therefore these TA systems were not detected.…”

Section: Discussionmentioning

confidence: 99%

A widespread toxin-antitoxin system exploiting growth control via alarmone signalling

Jimmy

Saha

Stavropoulos

et al. 2019

Preprint

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22Under stressful conditions, bacterial RelA-SpoT Homologue (RSH) enzymes synthesise the alarmone 23 (p)ppGpp, a nucleotide messenger. (p)ppGpp rewires bacterial transcription and metabolism to cope 24 with stress, and at high concentrations inhibits the process of protein synthesis and bacterial growth 25 to save and redirect resources until conditions improve. Single domain Small Alarmone Synthetases 26 (SASs) are RSH family members that contain the (p)ppGpp synthesis (SYNTH) domain, but lack the 27 hydrolysis (HD) domain and regulatory C-terminal domains of the long RSHs such as Rel, RelA and 28SpoT. We have discovered that multiple SAS subfamilies can be encoded in broadly distributed 29 conserved bicistronic operon architectures in bacteria and bacteriophages that are reminiscent of 30 those typically seen in toxin-antitoxin (TA) operons. We have validated five of these SASs as being 31 toxic (toxSASs), with neutralisation by the protein products of six neighbouring antitoxin genes. The 32 toxicity of Cellulomonas marina ToxSAS FaRel is mediated by alarmone accumulation combined with 33 depletion of cellular ATP and GTP pools, and this is counteracted by its HD domain-containing 34 antitoxin. Thus, the ToxSAS-antiToxSAS system is a novel TA paradigm comprising multiple different 35 antitoxins that exemplifies how ancient nucleotide-based signalling mechanisms can be repurposed 36 as TA modules during evolution, potentially multiple times independently. 37 1 Bacteria encounter a variety of different environmental conditions during their life cycles, to which 2 they need to respond and adapt in order to survive. This can include slowing down their growth and 3 redirecting their metabolic resources during nutritional stress, until conditions improve and the 4 growth rate can increase. One of the main signals that bacteria use for signalling stress are the 5 alarmone nucleotides ppGpp and pppGpp, collectively referred to as (p)ppGpp 1 . At high 6 concentrations (p)ppGpp is a potent inhibitor of bacterial growth 2 , targeting transcription, 7 translation and ribosome assembly 1 . (p)ppGpp is produced and degraded by proteins of the 8 RelA/SpoT homologue (RSH) superfamily, named after the two Escherichia coli representatives -9 multi-domain 'long' RSH factors RelA and SpoT 3 . In addition to long RSHs, bacteria can encode single-10 domain RSHs: Small Alarmone Synthetases (SAS) and Small Alarmone Hydrolases (SAH). 11It is currently unknown why some bacteria carry multiple SASs and SAHs, which can belong to many 12 different subfamilies. Conservation of gene order through evolution can reveal potentially interacting 13 proteins and shed light on the cellular role of proteins 4 . Therefore, we developed a computational 14 tool -FlaGs, standing for Flanking Genes 5 -for analysing the conservation of genomic 15 neighbourhoods, and applied it to our updated database of RSH sequences classified into 16 subfamilies. Surprisingly, we find that some subfamilies of SAS can be encoded in apparently bi-(and 17 sometimes tri-) ...

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Prediction of Type II Toxin-Antitoxin Loci in Klebsiella pneumoniae Genome Sequences

Cited by 22 publications

References 22 publications

Mechanisms of Bacterial Tolerance and Persistence in the Gastrointestinal and Respiratory Environments

Mechanisms of Bacterial Tolerance and Persistence in the Gastrointestinal and Respiratory Environments

Identification and characterization of acetyltransferase‐type toxin‐antitoxin locus in Klebsiella pneumoniae

A widespread toxin-antitoxin system exploiting growth control via alarmone signalling

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