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PubMed2001

Killing effect and antitoxic activity of the Leptospira interrogans toxin-antitoxin system in Escherichia coli.

We report the first evidence of a chromosome-encoded toxin-antitoxin locus in spirochetes. This locus has been found in the pathogenic spirochete Leptospira interrogans and exhibits homologies with the pem/chp loci. The L. interrogans chp locus consists of two genes: chpK (for "killer protein") and its upstream partner chpI (for "inhibitory protein"). Expression of ChpK in Escherichia coli results in the inhibition of bacterial growth. The coexpression of ChpI neutralizes ChpK toxicity. By Southern blot analysis, chp homologs were found in all representative pathogenic strains of L. interrogans.

Amino Acid Sequence↗
PubMed1985

Purification by high performance liquid chromatography of Clostridium perfringens type A enterotoxin prepared from high toxin producers selected by a toxin-antitoxin halo.

High enterotoxin-producing substrains of Clostridium perfringens type A were selected reproducibly as colonies having toxin-antitoxin haloes on agar plates of Duncan-Strong medium containing antitoxin serum. Enterotoxin from these substrains was subjected to rapid purification by high performance liquid chromatography (HPLC). For this, the toxin was extracted by sonication from sporulating bacteria grown in Duncan-Strong sporulation medium, fractionated by ammonium sulfate (40% saturation) precipitation and differential solubilization and then purified by HPLC: gel permeation chromatography through a G2000SW column and ion-exchange chromatography on a Mono Q column. Purified toxin preparations had a similar specific activity (4.2 X 10(2) mouse MLD/mg protein) and homogeneity on polyacrylamide gel-electrophoresis to preparations obtained by conventional gel permeation through a Sephadex-G200 column. By further HPLC on a Mono Q column, minor nontoxin proteins were separated from the toxin without loss of the toxicity on a protein basis. The final yield of the purified toxin was about 15% of that in the bacterial extract. The two HPLC procedures each took only one hour.

Animals↗
PubMed2005

Characteristics of Streptococcus mutans strains lacking the MazEF and RelBE toxin-antitoxin modules.

Two pairs of genes were identified in Streptococcus mutans with similarity to relBE and mazEF toxin-antitoxin (TA) modules of Escherichia coli. Transcription of mazEF and relBE was repressed by amino acid starvation, and relBE expression was repressed by low pH. Mutants lacking MazF, RelE, or both toxins (MRT1) grew in broth media and formed biofilms as well as the parent. Biofilm populations of MRT1 were more resistant to acid killing than the parent or single mutants. MRT1 also exhibited a longer diauxie during growth on glucose and inulin and displayed decreased phosphoenolpyruvate:sugar phosphotransferase activity. This is the first report that demonstrates a physiological role for TA modules in Gram-positive bacteria.

Bacterial Toxins↗
PubMed2006

TasA-tasB, a new putative toxin-antitoxin (TA) system from Bacillus thuringiensis pGI1 plasmid is a widely distributed composite mazE-doc TA system.

BACKGROUND: Post-segregational killing systems are present in a large variety of microorganisms. When found on plasmids, they are described as addiction systems that act to maintain the plasmid during the partitioning of the cell. The plasmid to be maintained through the generations harbours a group of two genes, one coding for a stable toxin and the other coding for an unstable antitoxin that inhibits the effects of the toxin. If, during cell division, the plasmid is lost, the toxin and antitoxin proteins present in the cytosol cease to be newly expressed. The level of unstable antitoxin protein then rapidly decreases, leaving the toxin free to act on the cellular target, leading to cell death. Consequently, only cells harbouring the plasmid can survive. RESULTS: The pGI1 plasmid of Bacillus thuringiensis H1.1 harbours a group of two genes, one showing similarities with the Doc toxin of the phd-doc toxin-antitoxin system, potentially coding for a toxin-antitoxin system. Attempts were made to clone this putative system in the Gram-negative host Escherichia coli. The putative antitoxin tasA was easily cloned in E. coli. However, although several combinations of DNA fragment were used in the cloning strategy, only clones containing a mutation in the toxin gene could be recovered, suggesting a toxic activity of TasB. An exhaustive search was carried out in order to index genes homologous to those of the putative tasA-tasB system among microorganisms. This study revealed the presence of this system in great number and in a large variety of microorganisms, either as tasA-tasB homologues or in association with toxins (or antitoxins) from other TA systems. CONCLUSION: In this work, we showed that the pGI1 plasmid of B. thuringiensis H1.1 harbours genes resembling a toxin-antitoxin system, named tasA-tasB for thuringiensis addiction system. This system appeared to be functional but unregulated in E. coli. Bioinformatics studies showed that the tasAB system is present on plasmids or chromosomes of a large variety of microorganisms. Moreover, the association between TasA antitoxin with toxins other than TasB (and vice versa) revealed the composite and modular nature of bacterial TA systems.

Amino Acid Sequence↗
PubMed2003

Toxin-antitoxin loci as stress-response-elements: ChpAK/MazF and ChpBK cleave translated RNAs and are counteracted by tmRNA.

Prokaryotic chromosomes encode toxin-antitoxin loci, often in multiple copies. In most cases, the function of these genes is not known. The chpA (mazEF) locus of Escherichia coli has been described as a cell killing module that induces bacterial apoptosis during nutritional stress. However, we found recently that ChpAK (MazF) does not confer cell killing but rather, induces a bacteriostatic condition from which the cells could be resuscitated. Results presented here yield a mechanistic explanation for the detrimental effect on cell growth exerted by ChpAK and the homologous ChpBK protein of E.coli. We show that both proteins inhibit translation by inducing cleavage of translated mRNAs. Consistently, the inhibitory effect of the proteins was counteracted by tmRNA. Amino acid starvation induced strong transcription of chpA that depended on Lon protease but not on ppGpp. Simultaneously, ChpAK cleaved tmRNA in its coding region. Thus, ChpAK and ChpBK inhibit translation by a mechanism very similar to that of E.coli RelE. On the basis of these results, we propose a model that integrates TA loci into general prokaryotic stress physiology.

ATP-Dependent Proteases↗
PubMed2006

Structure of FitAB from Neisseria gonorrhoeae bound to DNA reveals a tetramer of toxin-antitoxin heterodimers containing pin domains and ribbon-helix-helix motifs.

Neisseria gonorrhoeae is a sexually transmitted pathogen that initiates infections in humans by adhering to the mucosal epithelium of the urogenital tract. The bacterium then enters the apical region of the cell and traffics across the cell to exit into the subepithelial matrix. Mutations in the fast intracellular trafficking (fitAB) locus cause the bacteria to transit a polarized epithelial monolayer more quickly than the wild-type parent and to replicate within cells at an accelerated rate. Here, we describe the crystal structure of the toxin-antitoxin heterodimer, FitAB, bound to a high affinity 36-bp DNA fragment from the fitAB promoter. FitA, the antitoxin, binds DNA through its ribbon-helix-helix motif and is tethered to FitB, the toxin, to form a heterodimer by the insertion of a four turn alpha-helix into an extensive FitB hydrophobic pocket. FitB is composed of a PIN (PilT N terminus) domain, with a central, twisted, 5-stranded parallel beta-sheet that is open on one side and flanked by five alpha-helices. FitB in the context of the FitAB complex does not display nuclease activity against tested PIN substrates. The FitAB complex points to the mechanism by which antitoxins with RHH motifs can block the activity of toxins with PIN domains. Interactions between two FitB molecules result in the formation of a tetramer of FitAB heterodimers, which binds to the 36-bp DNA fragment and provides an explanation for how FitB enhances the DNA binding affinity of FitA.

Amino Acid Motifs↗
PubMed2006

Toxin-antitoxin systems are ubiquitous and plasmid-encoded in vancomycin-resistant enterococci.

Vancomycin-resistant enterococci (VRE) are common hospital pathogens that are resistant to most major classes of antibiotics. The incidence of VRE is increasing rapidly, to the point where over one-quarter of enterococcal infections in intensive care units are now resistant to vancomycin. The exact mechanism by which VRE maintains its plasmid-encoded resistance genes is ill-defined, and novel targets for the treatment of VRE are lacking. In an effort to identify novel protein targets for the treatment of VRE infections, we probed the plasmids obtained from 75 VRE isolates for the presence of toxin-antitoxin (TA) gene systems. Remarkably, genes for one particular TA pair, the mazEF system (originally identified on the Escherichia coli chromosome), were present on plasmids from 75/75 (100%) of the isolates. Furthermore, mazEF was on the same plasmid as vanA in the vast majority of cases (>90%). Plasmid stability tests and RT-PCR raise the possibility that this plasmid-encoded mazEF is indeed functional in enterococci. Given this ubiquity of mazEF in VRE and the deleterious activity of the MazF toxin, disruption of mazEF with pharmacological agents is an attractive strategy for tailored antimicrobial therapy.

Antitoxins↗
PubMed2005

The PIN-domain toxin-antitoxin array in mycobacteria.

PIN-domains (homologues of the pilT N-terminal domain) are small protein domains of approximately 140 amino acids. They are found in a diverse range of organisms and recent evidence from bioinformatics, biochemistry, structural biology and microbiology suggest that the majority of the prokaryotic PIN-domain proteins are the toxic components of toxin-antitoxin (TA) operons. Several microorganisms have a large cohort of these operons. For example, the genome of Mycobacterium tuberculosis encodes 48 PIN-domain proteins, of which 38 are thought to be involved in TA interactions. This large array of PIN-domain TA operons raises questions as to their evolutionary origin and contemporary functional significance. We suggest that the evolutionary origin of genes encoding mycobacterial PIN-domain TA operons is linked to the mobile gene pool, but that TA operons can become resident within the chromosome of host cells from where they might be recruited to fulfil a variety of roles associated with retardation of cell growth and persistence in stressful environments.

Adenosine Triphosphatases↗
PubMed2005

Plasmid p256 from Lactobacillus plantarum represents a new type of replicon in lactic acid bacteria, and contains a toxin-antitoxin-like plasmid maintenance system.

Lactobacillus plantarum NC7 harbours a single 7.2 kb plasmid called p256. This report describes the complete nucleotide sequence and annotation of p256, as well as the identification of the minimal replicon of the plasmid. Based on sequence features in the unusually small (0.7 kb) minimal replicon, and the absence of a gene for a replication-relevant protein, p256 seems to represent a hitherto unknown type of theta replicon in lactic acid bacteria (LAB), with a relatively low copy-number. In addition, a putative toxin-antitoxin (TA) locus was identified. Experiments with variants of p256 indicated that the TA system was involved in plasmid maintenance. Furthermore, controlled expression of the TA genes stabilized vectors derived from the p256 replicon. To the authors' knowledge, this is the first time a TA locus with a demonstrated plasmid maintenance function has been identified in LAB. Transformation of several LAB with plasmids derived from p256 indicated that it has a narrow host range. Several effective expression vectors based on the p256 replicon have been constructed.

Amino Acid Sequence↗