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Pangenomic and comprehensive analysis of the relationship between bacterial toxin-antitoxin systems and antibiotic phenotype

English title Pangenomic and comprehensive analysis of the relationship between bacterial toxin-antitoxin systems and antibiotic phenotype
Applicant Viollier Patrick
Number 160703
Funding scheme Sinergia
Research institution Dépt Microbiologie et Médecine Moléculaire Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Experimental Microbiology
Start/End 01.12.2015 - 30.11.2019
Approved amount 1'756'847.00
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All Disciplines (2)

Discipline
Experimental Microbiology
Medical Microbiology

Keywords (7)

RNAse; persistence; toxin-antitoxin systems; pangenomics; antibiotic phenotyping; RNA-Seq; bacteria

Lay Summary (German)

Lead
Bakterien regulieren ihr eigenes Wachstum mittels ausgeklügelter Überwachungssysteme, die der Klasse der Toxin-Antitoxin Systeme (TAS) angehören. TAS lassen sich oftmals anschalten sobald sich das Bakterium in einem Umfeld befindet, dass sich nicht zum Wachstum eignet zum Beispiel wenn Nährstoffmangel herrscht oder wenn sich Antibiotika oder andere wachstumshemmende Substanzen im Milieu befinden. Interessanterweise schützt die Verlangsamung des Wachstums durch TAS oftmals die Bakterien auch vor verschiedene antimikrobieller Wirkstoffe (Toleranz).
Lay summary

 Die molekulare Grundlage der Antibiotikatoleranz durch TAS ist noch unklar. Das Ziel dieses Projektes ist es die Mechanismen der Toleranz durch TAS aufzuklären und  die Wirkungsspektren und Aktivierungmechanismen der TAS zu charakterisieren, sowie mittels innovativer neuer genetischen Methoden der Systembiologie, neuartige TAS in verschiedenen Bakterien zu entdecken. Die Erkenntnisse dieser Studie dürften sich in der Bekämpfung neuer bakterieller Infektionen als nützlich erwiesen, begründet auf einer zweigleisigen anti-bakteriellen Strategie als Ansatzpunkt.

Direct link to Lay Summary Last update: 02.10.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Large-Scale Comparison of Toxin and Antitoxins in Listeria monocytogenes
Agüero José Antonio, Akarsu Hatice, Aguilar-Bultet Lisandra, Oevermann Anna, Falquet Laurent (2020), Large-Scale Comparison of Toxin and Antitoxins in Listeria monocytogenes, in Toxins, 12(1), 29-29.
HdaB: a novel and conserved DnaA-related protein that targets the RIDA process to stimulate replication initiation
Frandi Antonio, Collier Justine (2019), HdaB: a novel and conserved DnaA-related protein that targets the RIDA process to stimulate replication initiation, in Nucleic Acids Research, 000.
Structural insights into chaperone addiction of toxin-antitoxin systems
Guillet Valérie, Bordes Patricia, Bon Cécile, Marcoux Julien, Gervais Virginie, Sala Ambre Julie, Dos Reis Suzana, Slama Nawel, Mares-Mejía Israel, Cirinesi Anne-Marie, Maveyraud Laurent, Genevaux Pierre, Mourey Lionel (2019), Structural insights into chaperone addiction of toxin-antitoxin systems, in Nature Communications, 10(1), 782-782.
deltaRpkm: an R package for a rapid detection of differential gene presence between related bacterial genomes
Akarsu Hatice, Aguilar-Bultet Lisandra, Falquet Laurent (2019), deltaRpkm: an R package for a rapid detection of differential gene presence between related bacterial genomes, in BMC Bioinformatics, 20(1), 621-621.
TASmania: A bacterial Toxin-Antitoxin Systems database
Akarsu Hatice, Bordes Patricia, Mansour Moise, Bigot Donna-Joe, Genevaux Pierre, Falquet Laurent (2019), TASmania: A bacterial Toxin-Antitoxin Systems database, in PLOS Computational Biology, 15(4), e1006946-e1006946.
Directed evolution of SecB chaperones toward toxin-antitoxin systems
Sala Ambre Julie, Bordes Patricia, Ayala Sara, Slama Nawel, Tranier Samuel, Coddeville Michèle, Cirinesi Anne-Marie, Castanié-Cornet Marie-Pierre, Mourey Lionel, Genevaux Pierre (2017), Directed evolution of SecB chaperones toward toxin-antitoxin systems, in Proceedings of the National Academy of Sciences, 114(47), 12584-12589.
Cell Cycle Constraints and Environmental Control of Local DNA Hypomethylation in α-Proteobacteria
Ardissone Silvia, Redder Peter, Russo Giancarlo, Frandi Antonio, Fumeaux Coralie, Patrignani Andrea, Schlapbach Ralph, Falquet Laurent, Viollier Patrick H. (2016), Cell Cycle Constraints and Environmental Control of Local DNA Hypomethylation in α-Proteobacteria, in PLOS Genetics, 12(12), e1006499-e1006499.
Chaperone addiction of toxin–antitoxin systems
Bordes Patricia, Sala Ambre Julie, Ayala Sara, Texier Pauline, Slama Nawel, Cirinesi Anne-Marie, Guillet Valérie, Mourey Lionel, Genevaux Pierre (2016), Chaperone addiction of toxin–antitoxin systems, in Nature Communications, 7(1), 13339-13339.
Chaperone addiction of toxin-antitoxin systems
Bordes Patricia (2016), Chaperone addiction of toxin-antitoxin systems, in Nature Communications, 13339.
Growth control switch by a DNA-damageinducible toxin–antitoxin system in Caulobacter crescentus
Kirkpatrick Clare (2016), Growth control switch by a DNA-damageinducible toxin–antitoxin system in Caulobacter crescentus, in Nature Microbiology, 16008.

Scientific events



Self-organised

Title Date Place
Bugs, drugs and toxins 12.11.2018 Unige, Switzerland

Associated projects

Number Title Start Funding scheme
162716 Cell cycle-regulated surface structures in bacteria 01.10.2015 Project funding (Div. I-III)
173075 Chromosome methylation and maintenance in Caulobacter crescentus 01.04.2017 Project funding (Div. I-III)
127287 Molecular Basis of Cell Polarity and Division Control in Caulobacter crescentus 01.10.2009 Project funding (Div. I-III)

Abstract

One of the biggest threats to mankind is that of persistent pathogenic bacteria which are refractory to antibiotic therapy. Toxin-antitoxin systems (TAS) have emerged as key determinants of bacterial persistence/dormancy, antibiotic tolerance and virulence. They also control gene expression, biofilms, programmed cell death, retention of mobile genetic elements or plasmids, and protect from bacteriophages. This impressive functional diversity is easiest to reconcile with an underlying target-specific cleavage by (endonucleolytic) RNases, found in the vast majority of TAS. Bacterial genomes encode both a surprising diversity in different and a multiplicity in related RNase toxins (like RelE/HigB). As no comprehensive effort to elucidate the basis of such toxin specificity is yet done, we will study the molecular rules to re-wire TAS. The aims are to: A: Define the rules dictating the mRNA target site selection of RelE/HigB-type RNases of two unrelated bacterial lineages. We will also test if re-programming RelE/HigB-cleavage specificity will induce a commensurate change in antibiotic susceptibilities/tolerances upon sublethal toxin expression to correlate toxin activity with antibiotic phenotyping on a comprehensive scale.B: Determine which external triggers and cellular factors affect the expression/activity of the RelE/HigB-type and new toxins (identified below) using promoter reporters screened for antibiotic induction, single cell imaging, antitoxin/chaperone/ ribosome interaction and in vitro RNA cleavage assays. C: Uncover hitherto unknown TAS (possibly chaperone-controlled and/or other conserved) by unbiased forward genetics/genomics approaches. New TAS will be validated by genetics (mutational analyses) and complemented by bioinformatics/phylogeny to delineate the evolutionary history among them. A quartet of applicants from UNIGE (Patrick Viollier), UNIL (Justine Collier), UNIFR/SIB (Laurent Falquet) and CNRS/UPS-Toulouse (Pierre Genevaux) has teamed up to address these three tasks in a concerted and iterative fashion, relying on expertise in bacterial a) Seq-based molecular biology methods and forward genetics (PV), b) cell imaging and regulation (JC), c) TAS biochemistry (PG) and d) genome-based computational/bioinformatics skills (LF) who will develop an automated pipeline for biologists. Our integrative approaches and project will address themes of broad relevance and importance, ranging from fundamental science (TAS system discovery/phylogeny and molecular basis of RNase specificity) and clinically-relevant microbiology (antibiotic profiling of toxins) while also incorporating significant elements in technology development. Moreover, artificially modulating the expression of natural toxins may hold potential as a novel element to prevent resurrection of chronic bacterial infections. Lastly, re-programmed RelE/HigB RNAses could serve biotechnology as alternative gene silencing tools and could be used to develop sequence-specific RelE/HigB-derived ‘RNA restriction’ endonucleases, at least for widely-used in vitro molecular biology applications.
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