Avigdor Eldar

Tel Aviv University, Tell Afif, Tel Aviv, Israel

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Publications (24)323.62 Total impact

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    ABSTRACT: Bacterial quorum sensing enables bacteria to cooperate in a density-dependent manner via the group-wide secretion and detection of specific autoinducer molecules. Many bacterial species show high intraspecific diversity of autoinducer-receptor alleles, called pherotypes. The autoinducer produced by one pherotype activates its coencoded receptor, but not the receptor of another pherotype. It is unclear what selection forces drive the maintenance of pherotype diversity. Here, we use the ComQXPA system of Bacillus subtilis as a model system, to show that pherotype diversity can be maintained by facultative cheating-a minority pherotype exploits the majority, but resumes cooperation when its frequency increases. We find that the maintenance of multiple pherotypes by facultative cheating can persist under kin-selection conditions that select against "obligate cheaters" quorum-sensing response null mutants. Our results therefore support a role for facultative cheating and kin selection in the evolution of quorum-sensing diversity.
    No preview · Article · Jan 2016 · Proceedings of the National Academy of Sciences
  • Shaul Pollak · Shira Omer Bendori · Avigdor Eldar
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    ABSTRACT: Microorganisms adapt to the lab environment by eliminating unnecessary genetic systems. In Bacillus subtilis, such adaptation resulted in the lab strain being unable to form complex, matrix-associated structures known as biofilms. We recently showed that the ancestor of the lab strain, which is considered by the research community to be a stereotypical 'wild' strain, carries an atypical mutation in the RapP-PhrP quorum-sensing system. We have found that this mutation has profound effects on the biofilm phenotype of the ancestral strain. Here we discuss these recent findings and present more data that focuses on the lessons that can be learned from this work on the domestication of microorganisms.
    No preview · Article · Feb 2015 · Current Genetics
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    ABSTRACT: Antimicrobial cationic amphiphiles derived from aminoglycoside pseudo-oligosaccharide antibiotics interfere with the structure and function of bacterial membranes and offer a promising direction for the development of novel antibiotics. Herein, we report the design and synthesis of cationic amphiphiles derived from the pseudo-trisaccharide aminoglycoside tobramycin and its pseudo-disaccharide segment nebramine. Antimicrobial activity, membrane selectivity, mode of action, and structure-activity relationships were studied. Several cationic amphiphiles showed marked antimicrobial activity, and one amphiphilic nebramine derivative proved effective against all of the tested strains of bacteria; furthermore, against several of the tested strains, this compound was well over an order of magnitude more potent than the parent antibiotic tobramycin, the membrane-targeting antimicrobial peptide mixture gramicidin D, and the cationic lipopeptide polymyxin B, which are in clinical use. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    No preview · Article · Feb 2015 · Chemistry
  • Shira Omer Bendori · Shaul Pollak · Dorit Hizi · Avigdor Eldar
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    ABSTRACT: The genome of B. subtilis 168, encodes eight rap-phr quorum-sensing pairs. Rap proteins of all characterized Rap-Phr pairs inhibit the function of one or several important response regulators ComA; Spo0F or DegU. This inhibition is relieved upon binding of the peptide encoded by the cognate phr gene. Bacillus subtilis strain NCIB3610, the biofilm proficient ancestor of strain 168, encodes, in addition, the rapP-phrP pair on the plasmid pBS32. RapP was shown to dephosphorylate Spo0F and to regulate biofilm formation, but unlike other Rap-Phr pairs, RapP does not to interact with PhrP. In this work we extend the analysis of the RapP pathway by reexamining its transcriptional regulation, its effect on downstream targets and its interaction with PhrP. At the transcriptional level, we show that rapP and phrP regulation is similar to that of other rap-phr pairs. We further find that RapP has a Spo0F-independent negative effect on biofilm-related genes, which is mediated by the response regulator ComA. Finally, we find that the insensitivity of RapP to PhrP is due to a substitution of a highly conserved residue in the peptide binding domain of the rapP allele of strain NCIB3610. Reversing this substitution to the consensus amino-acid restores the PhrP-dependence of RapP activity and eliminates the effects of the rapP-phrP locus on ComA activity and biofilm formation. Taken together, our results suggest that RapP strongly repress biofilm formation through multiple targets and that PhrP does not counteract RapP due to a rare mutation in rapP. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
    No preview · Article · Nov 2014 · Journal of Bacteriology
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    Full-text · Article · Jan 2013 · Journal of Molecular Biology
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    ABSTRACT: Amphiphilic tobramycin analogues with potent antibacterial activity against tobramycin-resistant bacteria were synthesized. Most analogues were found to be less prone to deactivation by aminoglycoside-modifying enzymes than tobramycin. These compounds target the bacterial membrane rather than the ribosome. The lipophilic residue of these analogues is key to their antibacterial potency and selectivity towards bacterial membranes.
    Full-text · Article · Jun 2012 · Angewandte Chemie International Edition
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    ABSTRACT: Amphiphilic aminoglycoside antibiotics kill bacteria by disruption of their highly negatively charged membrane. In their Communication on page 5652 ff., M. Fridman, S. Garneau‐Tsodikova, and co‐workers report the synthesis of 6′′‐thioether tobramycin derivatives and show that their aliphatic chain acts as a drill bit that can rupture bacterial cells. These potent compounds evade many of the common bacterial resistance mechanisms, thereby opening a new avenue for the discovery of membrane‐targeting antibiotics.
    No preview · Article · Jun 2012 · Angewandte Chemie International Edition
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    ABSTRACT: Amphiphile Aminoglycosid‐Antibiotika töten Bakterien durch Zerstörung ihrer hoch negativ geladenen Membran. In der Zuschrift auf S. 5750 ff. beschreiben M. Fridman, S. Garneau‐Tsodikova et al. 6′′‐Thioether‐Tobramycin‐Derivate und zeigen, dass deren aliphatische Kette wie ein Bohrer wirkt, der Bakterienzellen aufbrechen kann. Diese wirksamen Verbindungen umgehen viele der gewöhnlichen bakteriellen Abwehrmechanismen und ebnen so einen neuen Weg für die Erforschung von Antibiotika, die die Membran angreifen.
    No preview · Article · Jun 2012 · Angewandte Chemie
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    ABSTRACT: Amphiphilic aminoglycoside antibiotics kill bacteria by disruption of their highly negatively charged membrane. In their Communication (DOI:10.1002/anie.201200761), M. Fridman and co-workers report the synthesis of 6''-thioether tobramycin derivatives and show that their aliphatic chain acts as a drill bit that can rupture bacterial cells. These potent compounds evade many of the common bacterial resistance mechanisms, thereby opening a new avenue for the discovery of membrane-targeting antibiotics.
    Full-text · Article · May 2012 · Angewandte Chemie International Edition
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    ABSTRACT: Signaling photoreceptors mediate diverse organismal adaptations in response to light. As light-gated protein switches, signaling photoreceptors provide the basis for optogenetics, a term that refers to the control of organismal physiology and behavior by light. We establish as novel optogenetic tools the plasmids pDusk and pDawn, which employ blue-light photoreceptors to confer light-repressed or light-induced gene expression in Escherichia coli with up to 460-fold induction upon illumination. Key features of these systems are low background activity, high dynamic range, spatial control on the 20-μm scale, independence from exogenous factors, and ease of use. In optogenetic experiments, pDusk and pDawn can be used to specifically perturb individual nodes of signaling networks and interrogate their role. On the preparative scale, pDawn can induce by light the production of recombinant proteins and thus represents a cost-effective and readily automated alternative to conventional induction systems.
    Full-text · Article · Mar 2012 · Journal of Molecular Biology
  • Peter Reuven · Avigdor Eldar
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    ABSTRACT: Bacterial phenotypic variability--the display of multiple distinct phenotypes in a genetically homogenous population of bacteria-emerges as an adaptive response to conflicting challenges. This creates an opportunity for social interactions which are able to dynamically redistribute cell fates within a community and to directly share the benefits of the different fates. While social interactions between cell fates can optimize community behavior, they also make the community vulnerable to exploitation. The aim of this review is to emphasize the social roles of phenotypic variability and introduce it as a communal rather than a single-cell property. Specifically, we present two prevalent perspectives on the forces shaping social interactions between cell fates--engineering optimality and social stability--and review recent works combining engineering, developmental and social evolution analyses in light of this distinction.
    No preview · Article · Dec 2011 · Current opinion in genetics & development
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    Avigdor Eldar
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    ABSTRACT: In microbial "quorum sensing" (QS) communication systems, microbes produce and respond to a signaling molecule, enabling a cooperative response at high cell densities. Many species of bacteria show fast, intraspecific, evolutionary divergence of their QS pathway specificity--signaling molecules activate cognate receptors in the same strain but fail to activate, and sometimes inhibit, those of other strains. Despite many molecular studies, it has remained unclear how a signaling molecule and receptor can coevolve, what maintains diversity, and what drives the evolution of cross-inhibition. Here I use mathematical analysis to show that when QS controls the production of extracellular enzymes--"public goods"--diversification can readily evolve. Coevolution is positively selected by cycles of alternating "cheating" receptor mutations and "cheating immunity" signaling mutations. The maintenance of diversity and the evolution of cross-inhibition between strains are facilitated by facultative cheating between the competing strains. My results suggest a role for complex social strategies in the long-term evolution of QS systems. More generally, my model of QS divergence suggests a form of kin recognition where different kin types coexist in unstructured populations.
    Preview · Article · Aug 2011 · Proceedings of the National Academy of Sciences
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    ABSTRACT: The hindguts of wood-feeding termites typically contain hundreds of microbial species. Together with their insect host, these gut microbes degrade lignocellulose into usable catabolites. Although past research revealed many facets of the stepwise flow of metabolites in this scheme, not much is known about the breadth of interactions occurring between termite-gut microbes. Most of these microbes are thought to depend on, and to have co-speciated with, their host and each other for millions of years. In this study, we explored the interactions of two spirochetes previously isolated from the very same termite species. As hydrogen (H_2) is the central free intermediate in termite-gut lignocellulose digestion, we focused on interactions between two closely related termite-gut spirochetes possessing complementary H_2 physiologies: one produces H_2, while the other consumes it. In vitro, these two Treponema species markedly enhanced each other's growth. RNA sequencing resolved the transcriptomes of these two closely related organisms, revealing that co-cultivation causes comprehensive changes in global gene expression. The expression of well over a 100 genes in each species was changed >twofold, with over a dozen changed >10-fold. Several changes implicating synergistic cross-feeding of known metabolites were validated in vitro. Additionally, certain activities beneficial to the host were preferentially expressed during consortial growth. However, the majority of changes in gene expression are not yet understandable, but indicate a broad, comprehensive and mutualistic interaction between these closely related, co-resident gut symbionts. The results suggest that staggeringly intricate networks of metabolic and gene interactions drive lignocellulose degradation and co-evolution of termite gut microbiota.
    No preview · Article · Jul 2011
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    [Show abstract] [Hide abstract]
    ABSTRACT: The hindguts of wood-feeding termites typically contain hundreds of microbial species. Together with their insect host, these gut microbes degrade lignocellulose into usable catabolites. Although past research revealed many facets of the stepwise flow of metabolites in this scheme, not much is known about the breadth of interactions occurring between termite-gut microbes. Most of these microbes are thought to depend on, and to have co-speciated with, their host and each other for millions of years. In this study, we explored the interactions of two spirochetes previously isolated from the very same termite species. As hydrogen (H(2)) is the central free intermediate in termite-gut lignocellulose digestion, we focused on interactions between two closely related termite-gut spirochetes possessing complementary H(2) physiologies: one produces H(2), while the other consumes it. In vitro, these two Treponema species markedly enhanced each other's growth. RNA sequencing resolved the transcriptomes of these two closely related organisms, revealing that co-cultivation causes comprehensive changes in global gene expression. The expression of well over a 100 genes in each species was changed >twofold, with over a dozen changed >10-fold. Several changes implicating synergistic cross-feeding of known metabolites were validated in vitro. Additionally, certain activities beneficial to the host were preferentially expressed during consortial growth. However, the majority of changes in gene expression are not yet understandable, but indicate a broad, comprehensive and mutualistic interaction between these closely related, co-resident gut symbionts. The results suggest that staggeringly intricate networks of metabolic and gene interactions drive lignocellulose degradation and co-evolution of termite gut microbiota.
    Full-text · Article · Feb 2011 · The ISME Journal
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    ABSTRACT: Compartmentalization of the activities of RNA polymerase sigma factors is a hallmark of formation of spores by Bacillus subtilis. It is initiated soon after the asymmetrically located sporulation division takes place with the activation of σF in the smaller cell, the prespore. σF then directs a signal via the membrane protease SpoIIGA to activate σE in the larger mother cell by processing of pro-σE. Here, we show that σE can be activated in the prespore with little effect on sporulation efficiency, implying that complete compartmentalization of σE activity is not essential for spore formation. σE activity in the prespore can be obtained by inducing transcription in the prespore of spoIIGA or of sigE*, which encodes a constitutively active form of σE, but not of spoIIGB, which encodes pro-σE. We infer that σE compartmentalization is partially attributed to a competition between the compartments for the activation signaling protein SpoIIR. Normally, SpoIIGA is predominantly located in the mother cell and as a consequence confines σE activation to it. In addition, we find that CsfB, previously shown to inhibit σG, is independently inhibiting σE activity in the prespore. CsfB thus appears to serve a gatekeeper function in blocking the action of two sigma factors in the prespore: it prevents σG from becoming active before completion of engulfment and helps prevent σE from becoming active at all.
    Preview · Article · Nov 2010 · Journal of bacteriology
  • Avigdor Eldar · Michael B. Elowitz
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    ABSTRACT: The genetic circuits that regulate cellular functions are subject to stochastic fluctuations, or ‘noise’, in the levels of their components. Noise, far from just a nuisance, has begun to be appreciated for its essential role in key cellular activities. Noise functions in both microbial and eukaryotic cells, in multicellular development, and in evolution. It enables coordination of gene expression across large regulons, as well as probabilistic differentiation strategies that function across cell populations. At the longest timescales, noise may facilitate evolutionary transitions. Here we review examples and emerging principles that connect noise, the architecture of the gene circuits in which it is present, and the biological functions it enables. We further indicate some of the important challenges and opportunities going forward.
    No preview · Article · Sep 2010 · Nature
  • Avigdor Eldar · Michael B Elowitz
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    ABSTRACT: The genetic circuits that regulate cellular functions are subject to stochastic fluctuations, or 'noise', in the levels of their components. Noise, far from just a nuisance, has begun to be appreciated for its essential role in key cellular activities. Noise functions in both microbial and eukaryotic cells, in multicellular development, and in evolution. It enables coordination of gene expression across large regulons, as well as probabilistic differentiation strategies that function across cell populations. At the longest timescales, noise may facilitate evolutionary transitions. Here we review examples and emerging principles that connect noise, the architecture of the gene circuits in which it is present, and the biological functions it enables. We further indicate some of the important challenges and opportunities going forward.
    No preview · Article · Sep 2010 · Nature
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    ABSTRACT: Development normally occurs similarly in all individuals within an isogenic population, but mutations often affect the fates of individual organisms differently. This phenomenon, known as partial penetrance, has been observed in diverse developmental systems. However, it remains unclear how the underlying genetic network specifies the set of possible alternative fates and how the relative frequencies of these fates evolve. Here we identify a stochastic cell fate determination process that operates in Bacillus subtilis sporulation mutants and show how it allows genetic control of the penetrance of multiple fates. Mutations in an intercompartmental signalling process generate a set of discrete alternative fates not observed in wild-type cells, including rare formation of two viable 'twin' spores, rather than one within a single cell. By genetically modulating chromosome replication and septation, we can systematically tune the penetrance of each mutant fate. Furthermore, signalling and replication perturbations synergize to significantly increase the penetrance of twin sporulation. These results suggest a potential pathway for developmental evolution between monosporulation and twin sporulation through states of intermediate twin penetrance. Furthermore, time-lapse microscopy of twin sporulation in wild-type Clostridium oceanicum shows a strong resemblance to twin sporulation in these B. subtilis mutants. Together the results suggest that noise can facilitate developmental evolution by enabling the initial expression of discrete morphological traits at low penetrance, and allowing their stabilization by gradual adjustment of genetic parameters.
    Full-text · Article · Aug 2009 · Nature
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    ABSTRACT: The Bacillus subtilis SpoVE integral membrane protein is essential for the heat resistance of spores, probably because of its involvement in spore peptidoglycan synthesis. We found that an SpoVE-yellow fluorescent protein (YFP) fusion protein becomes localized to the forespore during the earliest stages of engulfment, and this pattern is maintained throughout sporulation. SpoVE belongs to a well-conserved family of proteins that includes the FtsW and RodA proteins of B. subtilis. These proteins are involved in bacterial shape determination, although their function is not known. FtsW is necessary for the formation of the asymmetric septum in sporulation, and we found that an FtsW-YFP fusion localized to this structure prior to the initiation of engulfment in a nonoverlapping pattern with SpoVE-cyan fluorescent protein. Since FtsW and RodA are essential for normal growth, it has not been possible to identify loss-of-function mutations that would greatly facilitate analysis of their function. We took advantage of the fact that SpoVE is not required for growth to obtain point mutations in SpoVE that block the development of spore heat resistance but that allow normal protein expression and targeting to the forespore. These mutant proteins will be invaluable tools for future experiments aimed at elucidating the function of members of the SEDS (“shape, elongation, division, and sporulation”) family of proteins.
    Full-text · Article · Feb 2008 · Journal of bacteriology
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    Avigdor Eldar · Michael Elowitz
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    ABSTRACT: Why do cells of the same type, grown in the same conditions, look and behave so differently? Studying fluctuations in a well-characterized genetic pathway in yeast hints at how such variation arises.
    Preview · Article · Oct 2005 · Nature

Publication Stats

1k Citations
323.62 Total Impact Points

Institutions

  • 2011-2015
    • Tel Aviv University
      • Department of Molecular Microbiology and Biotechnology
      Tell Afif, Tel Aviv, Israel
  • 2009-2011
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States
  • 2005
    • California Institute of Technology
      • Division of Biology
      Pasadena, California, United States
  • 2003-2005
    • Weizmann Institute of Science
      • Department of Molecular Genetics
      Rechovot, Central District, Israel