DOCSLIB.ORG

Bacterial Programmed Cell Death Systems As Targets for Antibiotics

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Bacterial Programmed Cell Death Systems As Targets for Antibiotics Opinion TRENDS in Microbiology Vol.12 No.2 February 2004 Bacterial programmed cell death systems as targets for antibiotics Hanna Engelberg-Kulka, Boaz Sat, Myriam Reches, Shahar Amitai and Ronen Hazan Department of Molecular Biology, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel Growing experimental evidence has revealed the exist- encodes a labile antitoxin that interferes with the lethal ence of programmed cell death (PCD) systems in bac- action of the toxin. Such genetic toxin–antitoxin (TA) teria. Among these is the mazEF system, which is a systems for bacterial PCD have been studied in several regulable suicide module located on the chromosome laboratories, including those of Yarmolinsky [6], Couturier of E. coli and of some other bacteria, including patho- [7] and Gerdes [8]. The TA systems have been found gens. Several well-known antibiotics have recently mainly in E. coli on low-copy number plasmids (and some been found to cause cell death in E. coli by indirectly other extrachromosomal elements) where they are respon- activating this built-in suicide module. These antibiotics sible for the post-segregational killing effect [8]: the death belong to two groups: (i) inhibitors of transcription of cells from which these extra-chromosomal elements and/or translation; and (ii) inhibitors of folic acid metab- have been lost. Such a genetic unit has been termed an olism resulting in thymine starvation. These data, ‘addiction module’: it causes the cells to be ‘addicted’ to the together with the recent elucidation of the crystal struc- short-lived antitoxin product because its de novo synthesis ture of mazEF-directed components, hold promise for a is essential for cell survival [6]. Therefore, these modules rational chemical design of a new class of antibiotics have been implicated as having a role in maintaining the that directly activate chromosomal suicide modules by stability of the extra-chromosomal elements in the host on interacting with their components. Because multi-drug which they are borne [6–9]. resistance among bacterial pathogens is becoming Over the past decade, pairs of genes homologous to some more widespread, the results obtained might be useful of these extrachromosomally borne addiction modules as a basis for producing alternative drugs. have been found on the chromosome of E. coli and of various other bacteria [10–17]. The first addiction module From the late 1940s, the use of antibiotics to treat carried on a bacterial chromosome that was described as infectious diseases in humans and animals has drastically regulable and responsible for PCD was the E. coli mazEF disturbed microbial ecology [1,2]. In response to the threat module [13]. The mazEF system was described as a suicide of extinction, microbes have found genetic and biochemical module on the basis of its properties [18,19]. This module routes to develop resistance to every anti-microbial agent consists of two adjacent genes, mazE and mazF, located used to date. Resistance to these agents might develop downstream from the relA gene in the rel operon [10]. The through mutations of target sites or the acquisition of mazEF suicide module [13,20] has all the basic properties novel biochemical functions [1,2]. Therefore, the develop- that are required to be an addiction module: (i) MazF is ment of bacterial resistance to antibiotics can be seen as toxic and MazE is antitoxic; (ii) MazF is long-lived, the price that we are paying for medical progress. Perhaps whereas MazE is a labile protein degraded in vivo by the the only way that we might be permitted to continue to rely ATP-dependent ClpPA serine protease; (iii) MazE and on antibiotic therapy is through persistent efforts to MazF interact; (iv) MazE and MazF are co-expressed; and discover new antibiotics, and to identify additional (v) mazEF is negatively auto-regulated at the level of biochemical pathways as novel targets for their action. transcription by the combined action of both MazE and Here we describe the process of programmed cell death MazF proteins. Moreover, the mazEF chromosomal suicide (PCD) in bacteria as a newly discovered target for the module has unique characteristics that were not pre- action of antibiotics. viously described for the extrachromosomal addiction modules. Initially, it was found that mazEF transcription 0 0 Programmed cell death in bacteria is inhibited by guanosine 3 ,5 -bispyrophosphate (ppGpp) PCD refers to any form of cell death mediated by an [13], which is synthesized by the RelA protein under intracellular death program, no matter what triggers it conditions of extreme amino acid starvation [21]. On the and whether or not it displays all the characteristics of basis of these combined properties and the requirement for apoptosis [3–5]. In bacteria, one of the most studied PCD the continuous expression of MazE to prevent cell death, a systems is mediated through a unique genetic unit that model was proposed for PCD under conditions of nutrient consists of a pair of genes that specify two components. The starvation (Figure 1) [13]. This model was supported by second gene encodes a stable toxin, and the first gene results that showed that mazEF-mediated cell death is triggered by the artificial overproduction of ppGpp [13,22]. Corresponding author: Hanna Engelberg-Kulka ([email protected]). The other unique characteristics will be described below. www.sciencedirect.com 0966-842X/$ - see front matter q 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.tim.2003.12.008 Opinion TRENDS in Microbiology Vol.12 No.2 February 2004 67 Transcription P2 mazE mazF Translation ppGpp Toxin Antitoxin Antibiotics ClpPA protease Cell death TRENDS in Microbiology Figure 1. The ‘suicide module’ mazEF and how it can be activated. ppGpp (guanosine 30,50-bispyrophosphate) and antibiotics that inhibit transcription and/or translation triggers mazEF-dependent death. In each case, mazEF-expression is inhibited. Because MazE is a labile protein, its cellular concentration is reduced below the level required to antagonize the toxic MazF. Antibiotics that inhibit transcription and/or translation MazE falls so low that there is not enough to prevent the trigger mazEF-mediated cell death stable MazF from killing the cells (Figure 1). The described model for the activation of the mazEF suicide module was subsequently broadened to include Antibiotics that cause thymine starvation trigger the conditions under which RNA and protein synthesis is mazEF system and lead to cell death inhibited [18,23]. First, the effects on the system of several Recently, an additional group of antibiotics that induce antibiotics, including rifampicin, chloramphenicol and mazEF- mediated cell death was found [26]. These spectinomycin, were tested. Rifampicin inhibits RNA antibiotics, trimethoprim and the sulfonamide drugs synthesis (and subsequently protein synthesis) by binding cause thymine starvation. The effect of thymine starvation to the b-subunit of RNA polymerase [2]. Chloramphenicol on bacterial PCD deserves special attention because of its and spectinomycin inhibit protein synthesis by binding to wide implications and also its historical significance. As the A site of the 50S ribosomal subunit [2,24,25]. In wild- early as 1954, Cohen and Barner [27] discovered that a type cells, it was found that even briefly inhibiting thymine auxotrophic mutant (thyA)ofE. coli undergoes transcription and/or translation by these antibiotics was cell death in response to thymine starvation. This sufficient to induce mazEF-mediated death. By contrast, phenomenon, called thymineless death (TLD), is also deleting mazEF from the bacterial chromosome prevented found in many other organisms ranging from prokaryotes cell death in the presence of these antibiotics [18,19].It to eukaryotes [28]. TLD is a unique effect as starvation of should be noted that mazEF-dependent bacteriocidity of bacteria to other growth factors is bacteriostatic but not chloramphenicol and spectinomycin was observed when bactericidal. Although TLD has been investigated inten- cells were growing on a minimal but not a rich medium sively for almost 50 years, its molecular mechanism [18]. Therefore, it appears that the bacteriocidity of this remains unclear [28]. However, thymidine metabolism antibiotic depends on the environmental conditions. The and the coupled folic acid metabolism are well known proposal that the inhibition of translation triggers (Figure 2). Thymine starvation in E. coli can be induced in mazEF-mediated death was further supported by the several ways that inhibit the synthesis of thymidylate, results of experiments in which the phd-doc addiction either directly or indirectly, by interfering with folate module, borne on the P1 plasmid prophage, was used. It metabolism [28]. The synthetic antibacterial agents, was found that Doc protein, the toxic product of this trimethoprim and the sulfonamides, inhibit specific steps module, is a general inhibitor of translation and a trigger in the biosynthesis of tetrahydrofolate (Figure 2). of mazEF-mediated death [23]. Therefore, inhibiting As was recently described in E. coli, thymine starvation protein synthesis either by antibiotics or the Doc protein triggers mazEF-mediated cell death [26] (Figure 3). In triggers E. coli mazEF-mediated death; when the trans- these experiments, thymine starvation was induced in an lation of mazEF mRNA is inhibited, the level of the labile E. coli thyA auxotroph by omitting thymine from the www.sciencedirect.com 68 Opinion TRENDS in Microbiology Vol.12 No.2 February 2004 include sulfonamide drugs and trimethoprim, which by p-amino benzoic acid (PABA) inhibiting folic acid metabolism induce thymine starvation Sulfonamides leading to cell death. Dihydropteroic acid (DHPA) On the basis of the results showing that TLD depends on mazEF in E. coli, a model for the induction of mazEF-mediated cell death by thymine starvation was Folic acid suggested [26]. Previous research has shown that thymine starvation provokes DNA damage that involves a unique breaking or twisting of the chromosome into a configur- Dihydrofolic acid (DHFA) Trimethoprim ation that defies all the repair and protective mechanisms of the cell [29].
Load more

Recommended publications
  • Persistent Virus and Addiction Modules: an Engine of Symbiosis
    UC Irvine UC Irvine Previously Published Works Title Persistent virus and addiction modules: an engine of symbiosis. Permalink https://escholarship.org/uc/item/5ck1g026 Journal Current opinion in microbiology, 31 ISSN 1369-5274 Author Villarreal, Luis P Publication Date 2016-06-01 DOI 10.1016/j.mib.2016.03.005 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Available online at www.sciencedirect.com ScienceDirect Persistent virus and addiction modules: an engine of symbiosis Luis P Villarreal The giant DNA viruses are highly prevalent and have a particular host would occasionally survive but still retain a bit of affinity for the lytic infection of unicellular eukaryotic host. The the selfish virus DNA. Thus although parasitic selfish giant viruses can also be infected by inhibitory virophage which (virus-like) information is common in the genomes of all can provide lysis protection to their host. The combined life forms, its presence was explained as mostly defective protective and destructive action of such viruses can define a remnants of past plague sweeps that provides no func- general model (PD) of virus-mediated host survival. Here, I tional benefit to the host (e.g. junk). Until recently, this present a general model for role such viruses play in the explanation seemed satisfactory. In the last twenty years, evolution of host symbiosis. By considering how virus mixtures however, various observation-based developments have can participate in addiction modules, I provide a functional compelled us to re-evaluate this stance. Both comparative explanation for persistence of virus derived genetic ‘junk’ in genomics and metagenomics (sequencing habitats) has their host genomic habitats.
    [Show full text]
  • Srna Antitoxins: More Than One Way to Repress a Toxin
    Toxins 2014, 6, 2310-2335; doi:10.3390/toxins6082310 OPEN ACCESS toxins ISSN 2072-6651 www.mdpi.com/journal/toxins Review sRNA Antitoxins: More than One Way to Repress a Toxin Jia Wen and Elizabeth M. Fozo * Department of Microbiology, University of Tennessee, M409 Walters Life Sciences, Knoxville, TN 37996, USA; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-865-974-4028; Fax: +1-865-974-4007. Received: 30 June 2014; in revised form: 15 July 2014 / Accepted: 17 July 2014 / Published: 4 August 2014 Abstract: Bacterial toxin-antitoxin loci consist of two genes: one encodes a potentially toxic protein, and the second, an antitoxin to repress its function or expression. The antitoxin can either be an RNA or a protein. For type I and type III loci, the antitoxins are RNAs; however, they have very different modes of action. Type I antitoxins repress toxin protein expression through interacting with the toxin mRNA, thereby targeting the mRNA for degradation or preventing its translation or both; type III antitoxins directly bind to the toxin protein, sequestering it. Along with these two very different modes of action for the antitoxin, there are differences in the functions of the toxin proteins and the mobility of these loci between species. Within this review, we discuss the major differences as to how the RNAs repress toxin activity, the potential consequences for utilizing different regulatory strategies, as well as the confirmed and potential biological roles for these loci across bacterial species. Keywords: type I toxin-antitoxin; type III toxin-antitoxin; small RNA; small peptide 1.
    [Show full text]
  • Mechanisms of Plasmid Stable Maintenance with Special Focus on Plasmid Addiction Systems
    Vol. 48 No. 4/2001 1003–1023 QUARTERLY Review Mechanisms of plasmid stable maintenance with special focus on plasmid addiction systems. ½ Urszula Zielenkiewicz and Piotr Ceg³owski Institute of Biochemistry and Biophysics, Polish Academy of Sciences Received: 5 November, 2001, accepted: 24 November, 2001 Key words: plasmid addiction, post-segregational killing, partition; multimer resolution The stable inheritance of bacterial plasmids is achieved by a number of different mechanisms. Among them are resolution of plasmid oligomers into monomers, active plasmid partitioning into dividing cells and selective killing of plasmid-free segre- gants. A special focus is given to the last mechanism. It involves a stable toxin and an unstable antidote. The antidotes neutralize their cognate toxins or prevent their syn- thesis. The different decay rates of the toxins and the antidotes underlie molecular mechanisms of toxin activation in plasmid-free cells. By eliminating of plasmid-free cells from the population of plasmid-bearing ones the toxin-antidote couples therefore act as plasmid addiction systems. Plasmids are separate, autonomous genetic burgdorferi, Fraser et al., 1997; Bacillus cereus, elements present in a cell independently of Carlson & Kolstø, 1994). It is commonly ac- chromosomes. Most plasmids are small: from cepted that plasmid genes do not encode infor- several to 100 kb, but sometimes they are so mation indispensable for the functioning of large that using the size criteria their distinc- the host cell. However, plasmids specify nu- tion from the chromosome is difficult (e.g. in merous features advantageous for the host in Vibrio cholerae, Yamaichi et al., 1999; in specific environments, such as resistance to Rhizobium meliloti, Honeycutt et al., 1993).
    [Show full text]
  • Identification and Characterization of a Novel Toxin–Antitoxin Module From
    FEBS Letters 581 (2007) 1727–1734 Identification and characterization of a novel toxin–antitoxin module from Bacillus anthracis Shivangi Agarwala, Shivani Agarwalb, Rakesh Bhatnagara,* a School of Biotechnology, Jawaharlal Nehru University, New Delhi-110067, India b Gene Regulation Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi-110067, India Received 10 November 2006; revised 3 March 2007; accepted 20 March 2007 Available online 30 March 2007 Edited by Judit Ova´di (95–135 aa) [9]. When the bacterium looses the plasmid during Abstract Comparative genome analysis of Bacillus anthracis revealed a pair of linked genes encoding pemK (K, killer protein) a segregational event, the degradation of antitoxin by cellular and pemI (I, inhibitory protein) homologous to pem loci of other proteases renders the toxin free to execute its lethal effect. organisms. Expression of PemK in Escherichia coli and Bacillus Therefore, these modules have been implicated in maintaining anthracis was bacteriostatic whereas the concomitant expression the stability of extra-chromosomal elements in the host ensur- of PemI reversed the growth arrest. PemK expression effectively ing propagation of only plasmid-inherited population. The dif- inhibited protein synthesis with no significant effect on DNA rep- ferent decay rate of these toxins and antitoxins has been lication. Coexpression and interaction of these proteins con- envisioned to be the molecular basis of toxin activation in plas- firmed it to be a Type II addiction module. Thermal mid-free cells. Such a genetic unit has been termed as an denaturation analysis reflected poor conformational stability of ‘Addiction module’ because the cells become addicted to the PemI as compared to PemK.
    [Show full text]
  • Bacterial Plasmid Addiction Systems and Their Implications for Antibiotic
    PostDoc Journal Journal of Postdoctoral Research Vol. 5, No. 5, May 2017 www.postdocjournal.com Bacterial plasmid addiction systems and their implications for antibiotic drug development 1Jennifer Tsang, PhD 1 Beth Israel Deaconess Medical Center, Boston, MA 02115, USA *E-mail: [email protected] Abstract Bacteria frequently carry mobile genetic elements capable of being passed to other bacterial cells. An example of this is the transfer of plasmids (small, circular DNA molecules) that often contain antibiotic resistance genes from one bacterium to another. Plasmids have evolved mechanisms to ensure their survival through generations by employing plasmids segregation and replication machinery and plasmid addiction systems. Plasmid addiction systems utilize a post-segregational killing of cells that have not received a plasmid. In this review, the types of plasmid addiction systems are described as well as their prevalence in antibiotic resistant bacteria. Lastly, the possibility of targeting these plasmid addiction systems for the treatment of antibiotic resistant bacterial infections is explored. Keywords: plasmid, toxin-antitoxin system, plasmid addiction system, antibiotics, antimicrobial resistance Introduction Bacteria often carry mobile genetic elements divided between both daughter cells. However, capable of being passed from bacterium to low-copy number plasmids must use specific bacterium. One such element is the plasmid, a mechanisms to ensure that future cell small, circular, double-stranded DNA molecule. populations retain plasmids. For example, by Plasmids can be transferred to daughter cells random segregation a dividing cell with two upon replication (vertically transferred) or to copies of a plasmid has a 50% chance of both non-offspring cells (horizontally transferred). cells acquiring one plasmid and a 50% chance of Horizontal transfer of genetic material between one cell receiving both plasmids while the other bacterial cells can occur within the same or cell receives none.
    [Show full text]
  • Comparative Distribution of Antisense-RNA Regulated Toxin-Antitoxin 4 Systems
    bioRxiv preprint doi: https://doi.org/10.1101/060863; this version posted June 28, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 2 3 Comparative distribution of antisense-RNA regulated toxin-antitoxin 4 systems 5 6 Dorien S Coraya, Nicole Wheelera, Jack A Heinemanna,b, Paul P Gardnera,c 7 8 a. School of Biological Sciences, University of Canterbury, Christchurch NZ 9 b. Centre for Integrative Ecology 10 c. Address correspondence to Paul P Gardner, University of Canterbury, Private 11 Bag 4800 Christchurch, New Zealand; [email protected]. +64 3 12 364 2987 ext. 6742 13 14 Keywords: toxin-antitoxin systems, antisense RNA, post-segregational killing, 15 horizontal gene transfer 16 17 Abbreviations: toxin-antitoxin (TA); post-segregational killing (PSK); horizontal gene 18 transfer (HGT); mobile genetic elements (MGE); 19 1 bioRxiv preprint doi: https://doi.org/10.1101/060863; this version posted June 28, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 20 Abstract 21 Toxin-antitoxin (TA) systems are gene modules that appear to be widely 22 horizontally mobile. It has been proposed that type I TA systems, with an 23 antisense RNA-antitoxin, are less mobile than other TAs but no direct 24 comparisons have been made. We searched for type I, II and III toxin families on 25 chromosomes, plasmids and phages across bacterial phyla. The distribution of 26 type I TA systems were more narrow than most type II and III system families, 27 though this was less true of more recently discovered families.
    [Show full text]
  • Bacterial Addiction Module Toxin Doc Inhibits Translation Elongation Through Its Association with the 30S Ribosomal Subunit
    Bacterial addiction module toxin Doc inhibits translation elongation through its association with the 30S ribosomal subunit Mohan Liu*, Yonglong Zhang†, Masayori Inouye†, and Nancy A. Woychik*‡ Departments of *Molecular Genetics, Microbiology, and Immunology and †Biochemistry, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854 Communicated by Herbert Weissbach, Florida Atlantic University, Boca Raton, FL, December 19, 2007 (received for review October 29, 2007) Bacterial toxin–antitoxin (TA) systems (or ‘‘addiction modules’’) from their quasidormant state (4–6). Therefore, chromosomal TA typically facilitate cell survival during intervals of stress by induc- toxin action only leads to cell death (proposed to represent a type ing a state of reversible growth arrest. However, upon prolonged of programmed cell death distinct from apoptosis in eukaryotic stress, TA toxin action leads to cell death. TA systems have also systems) if and when the cell reaches the limit of its capacity to been implicated in several clinically important phenomena: biofilm either sustain quasidormancy and/or lose the ability to initiate the formation, bacterial persistence during antibiotic treatment, and synthesis of enough antitoxin to reverse toxin action upon release bacterial pathogenesis. TA systems harbored by pathogens also from stress. This pathway of bacterial programmed cell death has serve as attractive antibiotic targets. To date, the mechanism of been proposed to facilitate death of a subpopulation of damaged action of the majority of known TA toxins has not yet been cells to preserve food for the population as a whole, serve as a elucidated. We determined the mode of action of the Doc toxin of defense against the spread of bacteriophage infection, and act as a the Phd-Doc TA system.
    [Show full text]
  • Integrity and Stability of Virulence Plasmids from Pseudomonas Syringae Are Modulated by Mobile Genetic Elements and Multiple Toxin-Antitoxin Systems
    bioRxiv preprint doi: https://doi.org/10.1101/453399; this version posted October 25, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Integrity and stability of virulence plasmids from Pseudomonas syringae are modulated by mobile genetic elements and multiple toxin-antitoxin systems Leire Bardaji,1 Maite Añorga,1 Myriam Echeverría,1 Cayo Ramos,2 Jesús Murillo1* 1Institute for Multidisciplinary Applied Biology, Universidad Pública de Navarra, 31192 Mutilva, Spain 2Instituto de Hortofruticultura Subtropical y Mediterránea «La Mayora», Universidad de Málaga-CSIC, Área de Genética, Universidad de Málaga, Campus de Teatinos s/n, 29010 Málaga, Spain *Corresponding author: Jesús Murillo, jesus.murillo@ unavarra.es Keywords Postsegregational killing, plasmid evolution, IS801, replicative transposition, virulence, IS91 family, plasmid rearrangements Abstract Background: Virulence plasmids are critically exposed to genetic decay and loss, particularly in Pseudomonas syringae strains because of their high content of mobile genetic elements and their exploitation of environmental niches outside of the plant host. The demonstrated high plasticity and adaptability of P. syringae plasmids, involving the acquisition and loss of large DNA regions, contrasts with their usual high stability and the maintenance of key virulence genes in free living conditions. The identification of plasmid stability determinants and mechanisms will help to understand their evolution and adaptability to agroecosystems as well as to develop more efficient control measures. Results: We show that the three virulence plasmids of P.
    [Show full text]
  • A Parde-Family Toxin Antitoxin System in Major Resistance Plasmids Of
    www.nature.com/scientificreports OPEN A ParDE-family toxin antitoxin system in major resistance plasmids of Enterobacteriaceae confers Received: 20 February 2019 Accepted: 26 June 2019 antibiotic and heat tolerance Published: xx xx xxxx Muhammad Kamruzzaman1 & Jonathan Iredell1,2 Toxin-antitoxin (TA) systems were initially discovered as plasmid addiction systems on low-copy- number plasmids. Thousands of TA loci have since been identifed on chromosomes, plasmids and mobile elements in bacteria and archaea with diverse roles in bacterial physiology and in maintenance of genetic elements. Here, we identifed and characterised a plasmid mediated type II TA system in Enterobacteriaceae as a member of the ParDE super family. This system (hereafter, ParDEI) is distributed among IncI and IncF-type antibiotic resistance and virulence plasmids found in avian and human-source Escherichia coli and Salmonella. It is found that ParDEI is a plasmid stability and stress response module that increases tolerance of aminoglycoside, quinolone and β-lactam antibiotics in E. coli by ~100–1,000-fold, and thus to levels beyond those achievable in the course of antibiotic therapy for human infections. ParDEI also confers a clear survival advantage at 42 °C and expression of the ParEI toxin in trans induces the SOS response, inhibits cell division and promotes bioflm formation. This transmissible high-level antibiotic tolerance is likely to be an important factor in the success of the IncI and IncF plasmids which carry it and the important pathogens in which these are resident. Self-transferable (conjugative) antibiotic resistance plasmids promote their own retention in bacterial popula- tions via “addiction systems”, typically toxin-antitoxin (TA) modules that inhibit or kill plasmid-free daughter cells and serve to maintain plasmids in bacterial populations.
    [Show full text]
  • Antitoxin System in the Pvir Plasmid of Campylobacter Jejuni Rocky Damodar Patil Iowa State University
    Iowa State University Capstones, Theses and Graduate Theses and Dissertations Dissertations 2011 Identification and characterization of a toxin- antitoxin system in the pVir plasmid of Campylobacter jejuni Rocky Damodar Patil Iowa State University Follow this and additional works at: https://lib.dr.iastate.edu/etd Part of the Veterinary Preventive Medicine, Epidemiology, and Public Health Commons Recommended Citation Patil, Rocky Damodar, "Identification and characterization of a toxin-antitoxin system in the pVir plasmid of Campylobacter jejuni" (2011). Graduate Theses and Dissertations. 10297. https://lib.dr.iastate.edu/etd/10297 This Thesis is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Identification and characterization of a toxin-antitoxin system in the pVir plasmid of Campylobacter jejuni by Rocky Damodar Patil A thesis submitted to the graduate faculty in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE Major: Microbiology Program of Study Committee: Qijing Zhang, Major Professor Bryan Bellaire Aubrey Mendonca Iowa State University Ames, Iowa 2011 Copyright © Rocky Damodar Patil, 2011. All rights reserved. ii TABLE OF CONTENTS ABSTRACT ………………………………………………………………………………... iii CHAPTER 1. GENERAL INTRODUCTION
    [Show full text]
  • Toxin-Antitoxin Modules Are Pliable Switches Activated by Multiple Protease Pathways
    toxins Review Toxin-Antitoxin Modules Are Pliable Switches Activated by Multiple Protease Pathways Meenakumari Muthuramalingam, John C. White and Christina R. Bourne * Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA; [email protected] (M.M.); [email protected] (J.C.W.) * Correspondence: [email protected]; Tel.: +01-405-325-5348 Academic Editor: Anton Meinhart Received: 14 May 2016; Accepted: 27 June 2016; Published: 9 July 2016 Abstract: Toxin-antitoxin (TA) modules are bacterial regulatory switches that facilitate conflicting outcomes for cells by promoting a pro-survival phenotypic adaptation and/or by directly mediating cell death, all through the toxin activity upon degradation of antitoxin. Intensive study has revealed specific details of TA module functions, but significant gaps remain about the molecular details of activation via antitoxin degradation used by different bacteria and in different environments. This review summarizes the current state of knowledge about the interaction of antitoxins with cellular proteases Lon and ClpP to mediate TA module activation. An understanding of these processes can answer long-standing questions regarding stochastic versus specific activation of TA modules and provide insight into the potential for manipulation of TA modules to alter bacterial growth. Keywords: toxin-antitoxin; phenotypic changes; persister cells; post-segregational killing; bacterial physiology; environmental adaptation; cellular proteases; protease adaptors 1. Introduction Bacteria undergo complex adaptive metabolic changes to promote survival under stressful or harsh conditions. Toxin-antitoxin (TA) modules play crucial roles in bacterial immunity and in adaptation to the environment [1–3]. There is a growing interest in co-opting TA modules to control bacterial growth, but significant questions remain concerning the mechanisms of antitoxin degradation, which is required to promote adaptive changes [4–6].
    [Show full text]
  • Bacterial Type I Toxins: Folding and Membrane Interactions Sylvie Nonin-Lecomte, Laurence Fermon, Brice Felden, Marie-Laure Pinel-Marie
    Bacterial Type I Toxins: Folding and Membrane Interactions Sylvie Nonin-Lecomte, Laurence Fermon, Brice Felden, Marie-Laure Pinel-Marie To cite this version: Sylvie Nonin-Lecomte, Laurence Fermon, Brice Felden, Marie-Laure Pinel-Marie. Bacterial Type I Toxins: Folding and Membrane Interactions. Toxins, MDPI, 2021, 13 (7), pp.490. 10.3390/tox- ins13070490. hal-03286997 HAL Id: hal-03286997 https://hal.archives-ouvertes.fr/hal-03286997 Submitted on 15 Jul 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. toxins Review Bacterial Type I Toxins: Folding and Membrane Interactions Sylvie Nonin-Lecomte 1,† , Laurence Fermon 2,†, Brice Felden 2,‡ and Marie-Laure Pinel-Marie 2,* 1 CiTCoM, CNRS, UMR 8038, Université de Paris, 93526 Paris, France; [email protected] 2 BRM (Bacterial Regulatory RNAs and Medicine), Inserm, UMR_S 1230, Université de Rennes 1, 35000 Rennes, France; [email protected] (L.F.); [email protected] (B.F.) * Correspondence: [email protected] † These authors contributed equally. ‡ Deceased author. Abstract: Bacterial type I toxin-antitoxin systems are two-component genetic modules that encode a stable toxic protein whose ectopic overexpression can lead to growth arrest or cell death, and an unstable RNA antitoxin that inhibits toxin translation during growth.
    [Show full text]