Structural overview of toxin–antitoxin systems in infectious bacteria: A target for developing antimicrobial agents

Park, Sung Jean; Son, Woo Sung; Lee, Bong-Jin

doi:10.1016/j.bbapap.2013.02.027

Cited by 70 publications

(63 citation statements)

References 116 publications

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“…One of the approaches used to increase in vitro and in vivo stability and transmissibility of episomal bacterial plasmids is the introduction in the plasmid backbone of particular DNA sequences such as those constituting a Bbalanced-lethal^sys-tem also known as post-segregational killing (PSK) system (Mruk and Kobayashi 2014;Park et al 2013). These sequences code for short-lived antitoxin and for a long-lived and highly expressed toxin (toxin/antitoxin system, T/A), which is lethal for the bacterial cell, unless it is neutralized.…”

Section: Introductionmentioning

confidence: 99%

A stable luciferase reporter plasmid for in vivo imaging in murine models of Staphylococcus aureus infections

Bacconi

Haag

Torre

et al. 2015

Appl Microbiol Biotechnol

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In vivo imaging of bioluminescent bacteria permits their visualization in infected mice, allowing spatial and temporal evaluation of infection progression. Most available bioluminescent strains were obtained by integration of the luciferase genes into the bacterial chromosome, a challenging and time-consuming approach. Recently, episomal plasmids were used, which were introduced in bacteria and expressed all genes required for bioluminescence emission. However, the plasmid was progressively lost in vitro and in vivo, if bacteria were not maintained under antibiotic selective pressure. Increased stability could be obtained inserting into the plasmid backbone sequences that assured plasmid partition between daughter bacterial cells, or caused death of bacteria that had lost the plasmid. So far, no detailed analysis was performed of either plasmid stability in vivo or contribution of different stabilizing sequence types. Here we report the construction of a plasmid, which includes the Photorhabdus luminescens lux cassette expressed under the control of a Staphylococcus aureus specific gene promoter, and toxin/antitoxin (T/A) and partition sequences (Par) conferring stability and transmissibility of the plasmid. Following infection of mice with S. aureus carrying this plasmid, we demonstrated that the promoter-lux fusion was functional in vivo, that the plasmid was retained by 70-100% of bacterial cells 7 days post-infection, and that both stabilizing sequence types were required to maximize plasmid retention. These data suggest that the plasmid can be a valuable tool to study gene expression and bacterial spread in small laboratory animals infected with S. aureus or possibly other Gram-positive human pathogens.

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Section: Introductionmentioning

confidence: 99%

A stable luciferase reporter plasmid for in vivo imaging in murine models of Staphylococcus aureus infections

Bacconi

Haag

Torre

et al. 2015

Appl Microbiol Biotechnol

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“…One example is VapBC TA system, in which the VapC toxin is proposed to have metal-ion-dependent nuclease activity, and when TA system dissociates efficient binding between metal ion and the VapC toxin occurs. [36][37][38] Because of the direct involvement of TA systems in cell death, these systems have been targeted in the search for alternative antibiotics against multidrug-resistant bacteria. [39][40][41] However, in Helicobacter pylori, only two TA systems, HP0892-HP0893 and HP0894-HP0895, have been identified to date using bioinformatics 42 or determined experimentally.…”

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confidence: 99%

Crystal structure of toxin HP0892 from Helicobacter pylori with two Zn(II) at 1.8 Å resolution

Jang

Pathak

et al. 2014

Protein Science

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Antibiotic resistance and microorganism virulence have been consistently exhibited by bacteria and archaea, which survive in conditions of environmental stress through toxin-antitoxin (TA) systems. The HP0892-HP0893 TA system is one of the two known TA systems belonging to Helicobacter pylori. The antitoxin, HP0893, binds and inhibits the HP0892 toxin and regulates the transcription of the TA operon. Here, we present the crystal structure of the zinc-bound HP0892 toxin at 1.8 Å resolution. Reorientation of residues at the mRNase active site was shown. The involved residues, namely E58A, H86A, and H58A/ H60A, were mutated and the binding affinity was monitored by ITC studies. Through the structural difference between the apo and the metal-bound state, and using a homology modeling tool, the involvement of the metal ion in mRNase active site could be identified. The most catalytically important residue, His86, reorients itself to exhibit RNase activity. His47, Glu58, and His60 are involved in metal binding where Glu58 acts as a general base and His47 and His60 may also act as a general acid in enzymatic activity. Glu58 and Asp64 are involved in substrate binding and specific sequence recognition. Arg83 is involved in phosphate binding and stabilization of the transition state, and Phe90 is involved in base packing and substrate orientation.

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“…From the results, it was found that HP0894 may have a potential ribonuclease activity and represent the toxin-antitoxin (TA) system like RelE [50] and HP0892 also acts as a TA toxin with intrinsic RNase activity [51]. In a TA system, the toxin molecules are negative regulators which are harmful to cell due to cleavage of DNA or RNA, transfer of phosphate groups, phorphaorylation of proteins, inhibition of ATP synthesis and so on [52][53][54][55]. The antitoxin molecules are positive regulators which bind toxins themselves either on a gene or protein level, and regulate the activity of the toxin.…”

Section: Structure and Function Studies Of Hp0894 And Hp0892mentioning

confidence: 99%

NMR Study on Small Proteins from Helicobacter pylori for Antibiotic Target Discovery: A Review

2013

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Due to the widespread and increasing appearance of antibiotic resistance, a new strategy is needed for developing novel antibiotics. Especially, there are no specific antibiotics for Helicobacter pylori (H. pylori). H. pylori are bacteria that live in the stomach and are related to many serious gastric problems such as peptic ulcers, chronic gastritis, mucosa-associated lymphoid tissue lymphoma, and gastric cancer. Because of its importance as a human pathogen, it's worth studying the structure and function of the proteins from H. pylori. After the sequencing of the H. pylori strain 26695 in 1997, more than 1,600 genes were identified from H. pylori. Until now, the structures of 334 proteins from H. pylori have been determined. Among them, 309 structures were determined by X-ray crystallography and 25 structures by Nuclear Magnetic Resonance (NMR), respectively. Overall, the structures of large proteins were determined by X-ray crystallography and those of small proteins by NMR. In our lab, we have studied the structural and functional characteristics of small proteins from H. pylori. In this review, 25 NMR structures of H. pylori proteins will be introduced and their structure-function relationships will be discussed.

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Structural overview of toxin–antitoxin systems in infectious bacteria: A target for developing antimicrobial agents

Cited by 70 publications

References 116 publications

A stable luciferase reporter plasmid for in vivo imaging in murine models of Staphylococcus aureus infections

A stable luciferase reporter plasmid for in vivo imaging in murine models of Staphylococcus aureus infections

Crystal structure of toxin HP0892 from Helicobacter pylori with two Zn(II) at 1.8 Å resolution

NMR Study on Small Proteins from Helicobacter pylori for Antibiotic Target Discovery: A Review

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