Laurence Van Melderen- Université Libre de Bruxelles
Laurence Van Melderen
- Université Libre de Bruxelles
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Introduction
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Publications
Publications (143)
Formation and breakage of disulfide bridges strongly impacts folding and activity of proteins. Thioredoxin 1 (TrxA) is a small, conserved enzyme that reduces disulfide bonds in the bacterial cytosol. In this study, we provide an example of the emergence of a chaperone role for TrxA, which is independent of redox catalysis. We show that the activity...
Bactericidal antibiotics can cause metabolic perturbations that contribute to antibiotic-induced lethality. The molecular mechanism underlying these downstream effects remains unknown. Here, we show that ofloxacin, a fluoroquinolone that poisons DNA gyrase, induces a cascade of metabolic changes that are dependent on an active SOS response. We iden...
Toxin–antitoxin (TA) systems are small selfish genetic modules that increase vertical stability of their replicons. They have long been thought to stabilize plasmids by killing cells that fail to inherit a plasmid copy through a phenomenon called post-segregational killing (PSK) or addiction. While this model has been widely accepted, no direct obs...
Bacterial persistence to antibiotics defines the ability of small sub-populations of sensitive cells within an isogenic population to survive high doses of bactericidal antibiotics. Here, we investigated the importance of the five main envelope stress responses (ESRs) of Escherichia coli in persistence to five bactericidal β-lactam antibiotics by c...
Toxin-antitoxin (TA) systems are small selfish genetic modules that increase vertical stability of their replicons. They have long been thought to stabilize plasmids by killing cells that fail to inherit a plasmid copy through a phenomenon called post-segregational killing (PSK) or addiction. While this model has been widely accepted, no direct obs...
In this paper, we experimentally investigate the influence of the flow rate on the trajectory of ovoid and filamentous bacterial cells of E. coli in a low aspect ratio pinch flow fractionation device. To that aim, we vary the Reynolds number over two orders of magnitude, while monitoring the dynamics of the cells across our device. At low flow rate...
Antimicrobial resistance threatens the eradication of infectious diseases and impairs the efficacy of available therapeutics. The bacterial SOS pathway is a conserved response triggered by genotoxic stresses and represents one of the principal mechanisms that lead to resistance. The RecA recombinase acts as a DNA-damage sensor inducing the autoprot...
In a recent article, Balaban and colleagues developed the iTDtest allowing characterization of the type of interactions between different antibiotics at bactericidal concentrations (J.-F. Liu et al., mBio 13:e00004-22, 2022). This visual and semiquantitative assay is designed to determine how antibiotic cocktails affect tolerance and persistence, t...
Toxin–antitoxin systems are widespread in bacterial genomes. They are usually composed of two elements: a toxin that inhibits an essential cellular process and an antitoxin that counteracts its cognate toxin. In the past decade, a number of new toxin–antitoxin systems have been described, bringing new growth inhibition mechanisms to light as well a...
Transcriptional regulation of bacterial toxin-antitoxin (TA) systems allows compensation of toxin and antitoxin proteins to maintain a neutral state and avoid cell intoxication unless TA genes are lost. Such models have been primarily studied in plasmids, but TAs are equally present in other mobile genetic elements, such as transposons and prophage...
Persister cells are present at low frequency in isogenic populations. Moreover, they are only distinguishable from the bulk at the recovery time, after the antibiotic treatment. Therefore, time-lapse microscopy is the gold-standard method to investigate this phenomenon. Here, we describe an exhaustive procedure for acquiring single-cell data which...
Bacterial bloodstream infections (BSI) are a major health concern and can cause up to 40% mortality. Pseudomonas aeruginosa BSI is often of nosocomial origin and is associated with a particularly poor prognosis. The mechanism of bacterial persistence in blood is still largely unknown. Here, we analyzed the behavior of a cohort of clinical and labor...
s
Bacterial bloodstream infections (BSI) are a major health concern and can cause up to 40% mortality. Pseudomonas aeruginosa BSI is often of nosocomial origin and is associated with a particularly poor prognosis. The mechanism of bacterial persistence in blood is still largely unknown. Here, we analyzed the behavior of a cohort of clinical and lab...
Type II Toxin–antitoxin (TA) modules are bacterial operons that encode a toxic protein and its antidote, which form a self-regulating genetic system. Antitoxins put a halter on toxins in many ways that distinguish different types of TA modules. In type II TA modules, toxin and antitoxin are proteins that form a complex which physically sequesters t...
![Assigned [¹H,¹⁵N]-HSQC spectrum of YdaS in 20 mM sodium phosphate 150...](publication/336619899/figure/fig2/AS:962726385954829@1606543265507/Assigned-H-N-HSQC-spectrum-of-YdaS-in-20-mM-sodium-phosphate-150-mM-NaCl-pH-60-and_Q320.jpg)
The cryptic prophage CP-933P in Escherichia coli O157:H7 contains a parDE-like toxin–antitoxin module, the operator region of which is recognized by two flanking transcription regulators: PaaR2 (ParE associated Regulator), which forms part of the paaR2-paaA2-parE2 toxin–antitoxin operon and YdaS (COG4197), which is encoded in the opposite direction...
Transposable elements (TEs) are important in genetic diversification due to their recombination properties and their ability to promote horizontal gene transfer. Over the last decades, much effort has been made to understand TE transposition mechanisms and their impact on prokaryotic genomes. For example, the Tn 3 family is ubiquitous in bacteria,...
Type II toxin-antitoxin (TA) systems are small genetic elements composed of a toxic protein and its cognate antitoxin protein, the latter counteracting the toxicity of the former. While TA systems were initially discovered on plasmids, functioning as addiction modules through a phenomenon called post-segregational killing, they were later shown to...
There is growing controversy regarding the role of chromosomal toxin-antitoxin systems in bacterial physiology. mqsRA is a peculiar toxin-antitoxin system, as the gene encoding the toxin precedes that of the antitoxin. This system was previously shown to play a role in stress response and biofilm formation. In this work, we identified two promoters...
Burkholderia cenocepacia infections are difficult to treat due to resistance, biofilm formation and persistence. B. cenocepacia strain J2315 has a large multi-replicon genome (8.06 Mb) and the function of a large fraction of (conserved) hypothetical genes remains elusive. The goal of the present study is to elucidate the role of small proteins in B...
Much of the diversity of prokaryotic genomes is contributed by the tightly controlled recombination activity of transposons (Tn). The Tn 3 family is arguably one of the most widespread transposon families. Members carry a large range of passenger genes incorporated into their structures. Family members undergo replicative transposition using a DDE...
Toxin-antitoxin (TA) systems are small genetic modules comprising a stable toxic protein and an antitoxin preventing the toxin activity. In type II TA systems, antitoxins are unstable proteins that are degraded by host ATP-dependent proteases. In steady-state conditions, the antitoxin forms a complex with the toxin in which the toxic activity is in...
Bacterial persistence refers to the capacity of small subpopulations within clonal populations to tolerate antibiotics. Persisters are thought to originate from dormant cells in which antibiotic targets are less active and cannot be corrupted. Here, we report that in exponentially growing cultures, ofloxacin persisters originate from metabolically...
In Figure 2b, the minimal duration for killing (MDK) 99% of tolerant cells was erroneously labelled as MDK99.99 instead of MDK99. This has now been corrected in all versions of the Review. The publisher apologizes to the authors and to readers for this error.
Increasing concerns about the rising rates of antibiotic therapy failure and advances in single-cell analyses have inspired a surge of research into antibiotic persistence. Bacterial persister cells represent a subpopulation of cells that can survive intensive antibiotic treatment without being resistant. Several approaches have emerged to define a...
GCN5-related N-acetyl-transferase (GNAT)-like enzymes from toxin–antitoxin modules are strong inhibitors of protein synthesis. Here, we present the bases of the regulatory mechanisms of ataRT, a model GNAT-toxin–antitoxin module, from toxin synthesis to its action as a transcriptional de-repressor. We show the antitoxin (AtaR) traps the toxin (AtaT...
PaaR2 is a putative transcription regulator encoded by a three-component parDE-like toxin-antitoxin module from Escherichia coli O157:H7. Although this module's toxin, antitoxin, and toxin-antitoxin complex have been more thoroughly investigated, little remains known about its transcription regulator PaaR2. Using a wide range of biophysical techniq...
Background
Escherichia coli W3110 and a group of six isogenic derivatives, each displaying distinct specific rates of glucose consumption were characterized to determine levels of GFP production and population heterogeneity. These strains have single or combinatory deletions in genes encoding phosphoenolpyruvate:sugar phosphotransferase system (PTS...
Significance
In bacteria, small RNAs pair with target mRNAs to rapidly adjust gene expression in response to environmental and physiological changes. In this study, we identified a small RNA, SdhX, in Escherichia coli , whose expression is dependent on expression of tricarboxylic acid cycle genes. SdhX adjusts carbon flux by negatively regulating a...
The ataRT operon from enteropathogenic Escherichia coli encodes a toxin–antitoxin (TA) module with a recently discovered novel toxin activity. This new type II TA module targets translation initiation for cell-growth arrest. Virtually nothing is known regarding the molecular mechanisms of neutralization, toxin catalytic action or translation autore...
Persistence is a reversible and low-frequency phenomenon allowing a subpopulation of a clonal bacterial population to survive antibiotic treatments. Upon removal of the antibiotic, persister cells resume growth and give rise to viable progeny. Type II toxin-antitoxin (TA) systems were assumed to play a key role in the formation of persister cells i...
Toxin-‐antitoxin systems (TA) are widespread in bacteria and archea. They are commonly found in chromosomes and mobile genetic elements. These systems move from different genomic locations and bacterial hosts through horizontal gene transfer, using mobile elements as vehicles. Their potential roles in bacterial physiology are still a matter of deb...
Type II toxin-antitoxin (TA) systems are widespread in bacterial and archeal genomes. These modules are very dynamic and participate in bacterial genome evolution through horizontal gene transfer. TA systems are commonly composed of a labile antitoxin and a stable toxin. Toxins appear to preferentially inhibit the protein synthesis process. Toxins...
Toxin-antitoxin (TA) loci are prevalent in bacterial genomes. They are suggested to play a central role in dormancy and persister states. Under normal growth conditions, TA toxins are neutralized by their cognate antitoxins, and under stress conditions, toxins are freed and inhibit essential cellular processes using a variety of mechanisms. Here we...
Background/aims:
The Escherichia coli MazF is an endoribonuclease that cleaves mRNA at ACA sequences, thereby triggering inhibition of protein synthesis. The aim of this study is to evaluate the efficiency of the mazEF toxin-antitoxin system in plants to develop biotechnological tools for targeted cell ablation.
Methods:
A double transformation...
Many bacterial pathogens modulate their metabolic activity, virulence and pathogenicity through so-called 'toxin-antitoxin' (TA) modules. The genome of the human pathogen Escherichia coli O157 contains two three-component TA modules related to the known parDE module. Here, we show that the toxin EcParE2 maps in a branch of the RelE/ParE toxin super...
Monitoring persister cells can be extremely difficult due to their transient and stochastic nature, their low abundance, and their resemblance to Viable But Non-Culturable Cells (VBNCs). To date, the predominant method consists of determining the survival rate of a bacterial population after antibiotic treatment as a function of time or antibiotic...
We discovered a chromosomal locus containing two toxin-antitoxin modules (TAs) with an antisense transcriptional organization in the E. faecalis clinical isolate V583. These TAs are homologous to the type I txpA-ratA system and the type II mazEF, respectively. We have shown that the putative MazF is toxic for E. coli and triggers RNA degradation, a...
The present invention is related to a method for the selection of recombinant clones having integrated a gene of interest and a nucleotide sequence encoding a functional antidote protein to a toxic molecule, wherein said recombinant clones are the ones which survive following their integration into a host cell comprising in its genome a nucleotide...
The paaR2–paaA2–parE2 operon is a three-component toxin–antitoxin module encoded in the genome of the human pathogen Escherichia coli O157. The toxin (ParE2) and antitoxin (PaaA2) interact to form a nontoxic toxin–antitoxin complex. In this paper, the crystallization and preliminary characterization of two variants of the ParE2–PaaA2 toxin–antitoxi...
Streptococcus pyogenes ranks among the main causes of mortality from bacterial infections worldwide. Currently there is no vaccine to prevent diseases
such as rheumatic heart disease and invasive streptococcal infection. The streptococcal M protein that is used as the substrate
for epidemiological typing is both a virulence factor and a vaccine ant...
Antitoxins from prokaryotic type II toxin-antitoxin modules are characterized by a high degree of intrinsic disorder. The description of such highly flexible proteins is challenging because they cannot be represented by a single structure. Here, we present a combination of SAXS and NMR data to describe the conformational ensemble of the PaaA2 antit...
Toxin-antitoxin (TA) systems are small genetic modules usually composed of a toxin and an antitoxin counteracting the activity of the toxic protein. These systems are widely spread in bacterial and archaeal genomes. TA systems have been assigned many functions, ranging from persistence to DNA stabilization or protection against mobile genetic eleme...
Ribonucleoprotein complexes are essential regulatory components in bacteria. In this review, we focus on the carbon storage regulator (Csr) network, which is well conserved in the bacterial world. This regulatory network is composed of the CsrA master regulator, its targets and regulators. CsrA binds to mRNA targets and regulates translation either...
Escherichia coli is a highly versatile species, causing diverse intestinal and extraintestinal infections. Here, we present the complete genome
sequence of PMV-1, an O18:K1 extraintestinal pathogenic E. coli (ExPEC) strain that is used as a model for peritonitis in mice and was useful for deciphering the innate immune response
triggered by ExPEC in...
Several reports mention the presence of antibiotic resistance genes in natural and polluted environments, but many studies are based on their detection via polymerase chain reaction (PCR amplification of known genes and not on an activity screening. We constructed a metagenomic fosmid bank from DNA isolated from a polluted river in Brussels, Belgiu...
Genomic organization of the 39 ORFs present in the insert of the AmpR clone.
The complete list of the 39 ORFs detected in the insert of the AmpR clone.
Supplementary Table 1. Phage content of the isolates recovered from outside and inside the Concordia station. Supplementary material 2
Supplementary Fig. 1. Phylogenetic position of all isolates analyzed during this study among all Paenibacillus species type strains, based on 16S rRNA gene sequence analysis. Bootstrap branch confidence estimates are indicated. Supplementary material 1
Bacterial type II toxin-antitoxin systems are widespread in bacteria. Among them, the RelE toxin family is one of the most
abundant. The RelEK-12 toxin of Escherichia coli K-12 represents the paradigm for this family and has been extensively studied, both in vivo and in vitro. RelEK-12 is an endoribonuclease that cleaves mRNAs that are translated b...
Toxin-antitoxin (TA) systems have been reported in the genomes of most bacterial species, and their role when located on the
chromosome is still debated. TA systems are particularly abundant in the massive cassette arrays associated with chromosomal
superintegrons (SI). Here, we describe the characterization of two superintegron cassettes encoding...
Culturable psychrotolerant bacteria were isolated from the top snow on the high Antarctic Plateau surrounding the research station Concordia. A total of 80 isolates were recovered, by enrichment cultures, from two different isolation sites (a distant pristine site [75° S 123° E] and a site near the secondary runway of Concordia). All isolates were...
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The ccd F and parDE RK2 systems were originally identified on the E. coli F plasmid and on the RK2 broad-host-range plasmid, respectively. Early reports indicated that these two loci promote plasmid maintenance in growing population by killing daughter bacteria that did not inherit a plasmid copy at cell division by a mechanism termed ‘post-segrega...
Escherichia coli is a highly versatile species, causing diverse intestinal and extraintestinal infections. Here, we present the complete genome sequence of PMV-1, an O18:K1 extraintestinal pathogenic E. coli (ExPEC) strain that is used as a model for peritonitis in mice and was useful for deciphering the innate immune response triggered by ExPEC in...
Group A Streptococcus (GAS) M protein is an important virulence factor and potential vaccine antigen, and constitutes the basis for strain typing (emm-typing). Although >200 emm-types are characterized, structural data were obtained from only a limited number of emm-types. We aim to evaluate the sequence diversity of near-full-length M proteins fro...
This study describes for the first time heterogeneity of antibiotic resistance profiles among group A Streptococcus (GAS) isolates originating from a single throat swab in patients with acute pharyngitis. For each throat swab, ten GAS colonies were randomly selected from the primary plate and subcultured to a secondary plate. These isolates were ch...
Due to their crucial role in pathogenesis and virulence, phages of Staphylococcus aureus have been extensively studied. Most of them encode and disseminate potent staphylococcal virulence factors. In addition, their movements contribute to the extraordinary versatility and adaptability of this prominent pathogen by improving genome plasticity. In a...
Despite increasing interest in coagulase-negative staphylococci (CoNS), little information is available about their bacteriophages.
We isolated and sequenced three novel temperate Siphoviridae phages (StB12, StB27, and StB20) from the CoNS Staphylococcus hominis and S. capitis species. The genome sizes are around 40 kb, and open reading frames (ORF...
Streptococcus pneumoniae serotype 1 presents a high invasiveness index and is seldom isolated from its niche, the nasopharynx. We report an unusual carriage of serotype 1 carriage in a healthy pediatric population at the time of the heptavalent pneumococcal vaccine adoption in Belgium. Our sampling period coincides with an epidemic wave of serotype...
Bacterial persisters consist of a phenotypic subpopulation that survives antibiotic treatment, prolonging infection. The GhoT toxin from the newly discovered ghoS-ghoT toxin-antitoxin system contributes to persistence, most likely by interfering with bacterial inner membrane integrity.
Genetic manipulation has allowed the development of a strain of Escherichia coli with a higher biomass yield. The objective of this work is to understand the effect of the genetic manipulation at a macroscopic level, i.e. to derive a dynamic model of the evolution of the main macroscopic components of interest (substrate, biomass and products), and...
Escherichia coli O157 paaR2-paaA2-parE2 constitutes a unique three-component toxin-antitoxin (TA) module encoding a toxin (ParE2) related to the classic parDE family but with an unrelated antitoxin called PaaA2. The complex between PaaA2 and ParE2 was purified and characterized by analytical gel filtration, dynamic light scattering and small-angle...
Genetic manipulation has allowed the development of a strain of Escherichia coli with a higher biomass yield. The objective of this work is to understand the effect of the genetic manipulation at a macroscopic level, i.e. to derive a dynamic model of the evolution of the main macroscopic components of interest (substrate, biomass and products), and...
Toxin-antitoxin (TA) systems are composed of two elements: a toxic protein and an antitoxin which is either an RNA (type I and III) or a protein (type II). Type II systems are abundant in bacterial genomes in which they move via horizontal gene transfer. They are generally composed of two genes organized in an operon, encoding a toxin and a labile...
Genes for toxin-antitoxin (TA) complexes are widespread in prokaryote genomes, and species frequently possess tens of plasmid and chromosomal TA loci. The complexes are categorized into three types based on genetic organization and mode of action. The toxins universally are proteins directed against specific intracellular targets, whereas the antit...
Asymptomatic nasopharyngeal carriage represents an important biological marker for monitoring pneumococcal serotype distribution and evaluating vaccine effects. Serotype determination by conventional method (Quellung reaction) is technically and financially challenging. On the contrary, PCR-based serotyping represents a simple, economic and promisi...
The Mrr protein of Escherichia coli is a laterally acquired Type IV restriction endonuclease with specificity for methylated DNA. While Mrr nuclease activity
can be elicited by high-pressure stress in E. coli MG1655, its (over)expression per se does not confer any obvious toxicity. In this study, however, we discovered that Mrr of E. coli MG1655 ca...
Type II toxin–antitoxin (TA) systems are generally composed of two genes organized in an operon, encoding a labile antitoxin
and a stable toxin. They were first discovered on plasmids where they contribute to plasmid stability by a phenomenon denoted
as ‘addiction’, and subsequently in bacterial chromosomes. To discover novel families of antitoxins...
A novel temperate bacteriophage was isolated from a Bacillus cereus cereulide-producing strain and named vB_BceS-IEBH. vB_BceS-IEBH belongs to the Siphoviridae family. The complete genome sequence (53 kb) was determined and annotated. Eighty-seven ORFs were detected and for 28, a putative function was assigned using the ACLAME database. vB_BceS-IEB...
The Mrr protein of Escherichia coli is a laterally acquired Type IV restriction endonuclease with spe-cificity for methylated DNA. While Mrr nuclease activity can be elicited by high-pressure stress in E. coli MG1655, its (over)expression per se does not confer any obvious toxicity. In this study, however, we discovered that Mrr of E. coli MG1655 c...
Scarce data are available on Group A Streptococcus (GAS) antibiotic resistance in South America.
The antibiotic susceptibility patterns of GAS recovered from symptomatic children living in the central part of Brazil during a prospective epidemiological study were analyzed.
No isolates were resistant to penicillin or macrolides. Sixty-one percent of...
Clin Microbiol Infect 2011; 17: 907–914
A prospective cohort study of preschool healthy children (3–6 years old) from two distinct socio-economic settings in the Brussels area, Belgium, was conducted during the years 2006–2008. The objectives were to evaluate nasopharyngeal colonization by Streptococcus pneumoniae, Staphylococcus aureus, Moraxella...
Toxin-antitoxin (TA) systems are small genetic modules that are abundant in bacterial genomes. Three types have been described so far, depending on the nature and mode of action of the antitoxin component. While type II systems are surprisingly highly represented because of their capacity to move by horizontal gene transfer, type I systems appear t...
Global regulation allows bacteria to rapidly modulate the expression of a large variety of unrelated genes in response to environmental changes. Global regulators act at different levels of gene expression. This review focuses on CsrA, a post-transcriptional regulator that affects translation of its gene targets by binding mRNAs. CsrA controls a la...
Type II toxin-antitoxin (TA) systems are considered as protein pairs in which a specific toxin is associated with a specific antitoxin. We have identified a novel antitoxin family (paaA) that is associated with parE toxins. The paaA-parE gene pairs form an operon with a third component (paaR) encoding a transcriptional regulator. Two paralogous paa...
IntroductionGeneral Stress ResponseRegulation of σSConclusions
References
Rheumatic fever (RF) classically occurs after group A Streptococcus (GAS) pharyngitis in children aged over 5 years in developing countries. The present report describes the bacterial and host determinants in non-related toddlers who developed RF diagnostic criteria after toxic shock syndrome (TSS).
A 13-month-old boy and a 14-month-old girl presen...
