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https://www.readbyqxmd.com/read/28174313/atp-dependent-persister-formation-in-escherichia-coli
#1
Yue Shan, Autumn Brown Gandt, Sarah E Rowe, Julia P Deisinger, Brian P Conlon, Kim Lewis
: Persisters are dormant variants that form a subpopulation of cells tolerant to antibiotics. Persisters are largely responsible for the recalcitrance of chronic infections to therapy. In Escherichia coli, one widely accepted model of persister formation holds that stochastic accumulation of ppGpp causes activation of the Lon protease that degrades antitoxins; active toxins then inhibit translation, resulting in dormant, drug-tolerant persisters. We found that various stresses induce toxin-antitoxin (TA) expression but that induction of TAs does not necessarily increase persisters...
February 7, 2017: MBio
https://www.readbyqxmd.com/read/28167522/decreased-expression-of-stable-rna-can-alleviate-the-lethality-associated-with-rnase-e-deficiency-in-escherichia-coli
#2
P Himabindu, K Anupama
The endoribonuclease RNase E participates in mRNA degradation, rRNA processing and tRNA maturation in Escherichia coli, but the precise reasons for its essentiality are unclear and much debated. The enzyme is most active on RNA substrates with a 5' -terminal monophosphate, which is sensed by a domain in the enzyme that includes residue R169; E. coli also possesses a 5' -pyrophosphohydrolase RppH that catalyses conversion of 5' -terminal-triphosphate to -monophosphate on RNAs. Although the C-terminal half (CTH), beyond residue approximately 500, of RNase E is dispensable for viability, the ΔCTH mutation is lethal when combined with an R169Q mutation or with deletion of rppH In this work, we show that both these lethalities can be rescued in derivatives in which four, or five, of the seven rrn operons in the genome have been deleted...
February 6, 2017: Journal of Bacteriology
https://www.readbyqxmd.com/read/28164379/peptide-nucleotide-antibiotic-microcin-c-is-a-potent-inducer-of-stringent-response-and-persistence-in-both-sensitive-and-producing-cells
#3
Julia Piskunova, Etienne Maisonneuve, Elsa Germain, Kenn Gerdes, Konstantin Severinov
Microcin C (McC) is a peptide-nucleotide antibiotic that inhibits aspartyl-tRNA synthetase. Here, we show that McC is a strong inducer of persistence in Escherichia coli. Persistence induced by McC is mediated by (p)ppGpp and requires chromosomally encoded toxin-antitoxin modules. McC-producing cells have increased persistence levels due to a combined effect of McC imported from the cultured medium and intracellularly synthesized antibiotic. McC-producing cells also induce persistence in sensitive cells during co-cultivation, underscoring complex interactions in bacterial communities where an antagonistic compound produced by one community member can benefit other members by increasing their ability to withstand antibiotics...
February 6, 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28157202/molecular-mutagenesis-of-ppgpp-turning-a-rela-activator-into-an-inhibitor
#4
Jelena Beljantseva, Pavel Kudrin, Steffi Jimmy, Marcel Ehn, Radek Pohl, Vallo Varik, Yuzuru Tozawa, Victoria Shingler, Tanel Tenson, Dominik Rejman, Vasili Hauryliuk
The alarmone nucleotide (p)ppGpp is a key regulator of bacterial metabolism, growth, stress tolerance and virulence, making (p)ppGpp-mediated signaling a promising target for development of antibacterials. Although ppGpp itself is an activator of the ribosome-associated ppGpp synthetase RelA, several ppGpp mimics have been developed as RelA inhibitors. However promising, the currently available ppGpp mimics are relatively inefficient, with IC50 in the sub-mM range. In an attempt to identify a potent and specific inhibitor of RelA capable of abrogating (p)ppGpp production in live bacterial cells, we have tested a targeted nucleotide library using a biochemical test system comprised of purified Escherichia coli components...
February 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28138140/hit-the-right-spots-cell-cycle-control-by-phosphorylated-guanosines-in-alphaproteobacteria
#5
REVIEW
Régis Hallez, Marie Delaby, Stefano Sanselicio, Patrick H Viollier
The class Alphaproteobacteria includes Gram-negative free-living, symbiotic and obligate intracellular bacteria, as well as important plant, animal and human pathogens. Recent work has established the key antagonistic roles that phosphorylated guanosines, cyclic-di-GMP (c-di-GMP) and the alarmones guanosine tetraphosphate and guanosine pentaphosphate (collectively referred to as (p)ppGpp), have in the regulation of the cell cycle in these bacteria. In this Review, we discuss the insights that have been gained into the regulation of the initiation of DNA replication and cytokinesis by these second messengers, with a particular focus on the cell cycle of Caulobacter crescentus...
January 31, 2017: Nature Reviews. Microbiology
https://www.readbyqxmd.com/read/28115345/sub-inhibitory-concentrations-of-bacteriostatic-antibiotics-induce-rela-dependent-and-rela-independent-tolerance-to-%C3%AE-lactams
#6
Pavel Kudrin, Vallo Varik, Sofia Raquel Alves Oliveira, Jelena Beljantseva, Teresa Del Peso Santos, Ievgen Dzhygyr, Dominik Rejman, Felipe Cava, Tanel Tenson, Vasili Hauryliuk
The nucleotide (p)ppGpp is a key regulator of bacterial metabolism, growth, stress tolerance and virulence. During amino acid starvation, the Escherichia coli (p)ppGpp synthetase RelA is activated by deacylated tRNA in the ribosomal A-site. An increase in (p)ppGpp is believed to drive the formation of antibiotic-tolerant persister cells, prompting the development of strategies to inhibit (p)ppGpp synthesis. We show that in a biochemical system from purified E. coli components, the antibiotic thiostrepton efficiently inhibits RelA activation by the A-site tRNA...
January 23, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28067906/prophage-mediated-defence-against-viral-attack-and-viral-counter-defence
#7
Rebekah M Dedrick, Deborah Jacobs-Sera, Carlos A Guerrero Bustamante, Rebecca A Garlena, Travis N Mavrich, Welkin H Pope, Juan C Cervantes Reyes, Daniel A Russell, Tamarah Adair, Richard Alvey, J Alfred Bonilla, Jerald S Bricker, Bryony R Brown, Deanna Byrnes, Steven G Cresawn, William B Davis, Leon A Dickson, Nicholas P Edgington, Ann M Findley, Urszula Golebiewska, Julianne H Grose, Cory F Hayes, Lee E Hughes, Keith W Hutchison, Sharon Isern, Allison A Johnson, Margaret A Kenna, Karen K Klyczek, Catherine M Mageeney, Scott F Michael, Sally D Molloy, Matthew T Montgomery, James Neitzel, Shallee T Page, Marie C Pizzorno, Marianne K Poxleitner, Claire A Rinehart, Courtney J Robinson, Michael R Rubin, Joseph N Teyim, Edwin Vazquez, Vassie C Ware, Jacqueline Washington, Graham F Hatfull
Temperate phages are common, and prophages are abundant residents of sequenced bacterial genomes. Mycobacteriophages are viruses that infect mycobacterial hosts including Mycobacterium tuberculosis and Mycobacterium smegmatis, encompass substantial genetic diversity and are commonly temperate. Characterization of ten Cluster N temperate mycobacteriophages revealed at least five distinct prophage-expressed viral defence systems that interfere with the infection of lytic and temperate phages that are either closely related (homotypic defence) or unrelated (heterotypic defence) to the prophage...
January 9, 2017: Nature Microbiology
https://www.readbyqxmd.com/read/28056744/nucleotide-second-messenger-signaling-as-a-target-for-the-control-of-bacterial-biofilm-formation
#8
Alberto J Martín-Rodríguez, Ute Römling
Bacterial biofilm formation and associated phenotypes are the major cause of chronic infection in humans. The major regulator of biofilm formation in Gram-negative and Gram-positive bacteria are nucleotide-based second messenger signaling pathways. Nucleotide-based signaling is a ubiquitous signal transduction mechanism in all domains of life that relay changes in the extracellular or intracellular milieu to protein or RNA effectors, leading to adaptive physiological responses. To date, six bona fide nucleotide signaling pathways, (p)ppGpp, cAMP, cGMP, c-di-AMP, c-di-GMP and cGAMP, have been characterized with respect to basic pathway modules and phenotypic and physiological output...
January 5, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28049149/rela-mutant-enterococcus-faecium-with-multiantibiotic-tolerance-arising-in-an-immunocompromised-host
#9
Erin S Honsa, Vaughn S Cooper, Mohammed N Mhaissen, Matthew Frank, Jessica Shaker, Amy Iverson, Jeffrey Rubnitz, Randall T Hayden, Richard E Lee, Charles O Rock, Elaine I Tuomanen, Joshua Wolf, Jason W Rosch
: Serious bacterial infections in immunocompromised patients require highly effective antibacterial therapy for cure, and thus, this setting may reveal novel mechanisms by which bacteria circumvent antibiotics in the absence of immune pressure. Here, an infant with leukemia developed vancomycin-resistant Enterococcus faecium (VRE) bacteremia that persisted for 26 days despite appropriate antibiotic therapy. Sequencing of 22 consecutive VRE isolates identified the emergence of a single missense mutation (L152F) in relA, which constitutively activated the stringent response, resulting in elevated baseline levels of the alarmone guanosine tetraphosphate (ppGpp)...
January 3, 2017: MBio
https://www.readbyqxmd.com/read/28024527/in-silico-prediction-of-dual-function-of-dksa-like-hypothetical-protein-in-v-cholerae-o395-genome
#10
Avirup Dutta, Atul Katarkar, Keya Chaudhuri
Cholera, an acute infection of the small intestine, is caused by Vibrio cholerae. The present study identified a hypothetical protein in V. cholerae O395, which was predicted to be acquired through horizontal gene transfer the origin of which was found to be from a phage. Its expression was further confirmed by RT-PCR. Homology based 3D model of the hypothetical protein indicated DksA like homologue. Protein binding site of 3D-model revealed a deep cleft which may influence the dimer formation and interaction with ds-DNA molecule...
January 2017: Microbiological Research
https://www.readbyqxmd.com/read/27986825/vitamin-c-targets-p-ppgpp-synthesis-leading-to-stalling-of-long-term-survival-and-biofilm-formation-in-m-smegmatis
#11
Kirtimaan Syal, Neerupma Bhardwaj, Dipankar Chatterji
Earlier, Vitamin C was demonstrated to sterilize Mycobacterium tuberculosis culture via Fenton's reaction at high concentration. It alters the regulatory pathways associated with stress response and dormancy. Since (p)ppGpp is considered to be the master regulator of stress response and is responsible for bacterial survival under stress, we tested the effect of Vitamin C on the formation of (p)ppGpp. In-vivo estimation of (p)ppGpp showed a decrease in (p)ppGpp levels in Vitamin C treated M. smegmatis cells in comparison to the untreated cells...
December 15, 2016: FEMS Microbiology Letters
https://www.readbyqxmd.com/read/27980159/mechanisms-of-bacterial-persistence-during-stress-and-antibiotic-exposure
#12
REVIEW
Alexander Harms, Etienne Maisonneuve, Kenn Gerdes
Bacterial persister cells avoid antibiotic-induced death by entering a physiologically dormant state and are considered a major cause of antibiotic treatment failure and relapsing infections. Such dormant cells form stochastically, but also in response to environmental cues, by various pathways that are usually controlled by the second messenger (p)ppGpp. For example, toxin-antitoxin modules have been shown to play a major role in persister formation in many model systems. More generally, the diversity of molecular mechanisms driving persister formation is increasingly recognized as the cause of physiological heterogeneity that underlies collective multistress and multidrug tolerance of persister subpopulations...
December 16, 2016: Science
https://www.readbyqxmd.com/read/27956500/inhibiting-translation-elongation-can-aid-genome-duplication-in-escherichia-coli
#13
Kamila K Myka, Michelle Hawkins, Aisha H Syeda, Milind K Gupta, Caroline Meharg, Mark S Dillingham, Nigel J Savery, Robert G Lloyd, Peter McGlynn
Conflicts between replication and transcription challenge chromosome duplication. Escherichia coli replisome movement along transcribed DNA is promoted by Rep and UvrD accessory helicases with Δrep ΔuvrD cells being inviable under rapid growth conditions. We have discovered that mutations in a tRNA gene, aspT, in an aminoacyl tRNA synthetase, AspRS, and in a translation factor needed for efficient proline-proline bond formation, EF-P, suppress Δrep ΔuvrD lethality. Thus replication-transcription conflicts can be alleviated by the partial sacrifice of a mechanism that reduces replicative barriers, namely translating ribosomes that reduce RNA polymerase backtracking...
December 11, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27933045/what-is-the-link-between-stringent-response-endoribonuclease-encoding-type-ii-toxin-antitoxin-systems-and-persistence
#14
Bhaskar C M Ramisetty, Dimpy Ghosh, Maoumita Roy Chowdhury, Ramachandran S Santhosh
Persistence is a transient and non-inheritable tolerance to antibiotics by a small fraction of a bacterial population. One of the proposed determinants of bacterial persistence is toxin-antitoxin systems (TASs) which are also implicated in a wide range of stress-related phenomena. Maisonneuve E, Castro-Camargo M, Gerdes K. 2013. Cell 154:1140-1150 reported an interesting link between ppGpp mediated stringent response, TAS, and persistence. It is proposed that accumulation of ppGpp enhances the accumulation of inorganic polyphosphate which modulates Lon protease to degrade antitoxins...
2016: Frontiers in Microbiology
https://www.readbyqxmd.com/read/27931778/a-magic-spot-in-genome-maintenance
#15
REVIEW
Aviram Rasouly, Bibhusita Pani, Evgeny Nudler
Nucleotide excision repair (NER) is the key DNA repair system that eliminates the majority of DNA helix-distorting lesions. RNA polymerase (RNAP) expedites the recognition of DNA damage by NER components via transcription-coupled DNA repair (TCR). In bacteria, a modified nucleotide ppGpp ('magic spot') is a pleiotropic second messenger that mediates the response to nutrient deficiencies by altering the initiation properties of RNAP. In this review, we discuss newly elucidated roles of guanosine 5'-diphosphate 3'-diphosphate (ppGpp) in transcription elongation that couple this alarmone to DNA damage repair and maintenance...
January 2017: Trends in Genetics: TIG
https://www.readbyqxmd.com/read/27915292/the-dual-role-of-dksa-protein-in-the-regulation-of-escherichia-coli-pargx-promoter
#16
Robert Łyżeń, Amarnath Maitra, Klaudia Milewska, Maja Kochanowska-Łyżeń, V James Hernandez, Agnieszka Szalewska-Pałasz
Gene expression regulation by the stringent response effector, ppGpp, is facilitated by DksA protein; however DksA and ppGpp can play independent roles in transcription. In Escherichia coli, the pArgX promoter which initiates the transcription of four tRNA genes was shown to be inhibited by ppGpp. Our studies on the role of DksA in pArgX regulation revealed that it can stimulate transcription by increasing the binding of RNA polymerase to the promoter and the productive transcription complex formation. However, when DksA is present together with ppGpp a severe down-regulation of promoter activity is observed...
December 1, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27903898/transfer-rna-is-highly-unstable-during-early-amino-acid-starvation-in-escherichia-coli
#17
Sine Lo Svenningsen, Mette Kongstad, Thomas Søndergaard Stenum, Ana J Muñoz-Gómez, Michael A Sørensen
Due to its long half-life compared to messenger RNA, bacterial transfer RNA is known as stable RNA. Here, we show that tRNAs become highly unstable as part of Escherichia coli's response to amino acid starvation. Degradation of the majority of cellular tRNA occurs within twenty minutes of the onset of starvation for each of several amino acids. Both the non-cognate and cognate tRNA for the amino acid that the cell is starving for are degraded, and both charged and uncharged tRNA species are affected. The alarmone ppGpp orchestrates the stringent response to amino acid starvation...
November 29, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27900286/selective-and-efficient-elimination-of-vibrio-cholerae-with-a-chemical-modulator-that-targets-glucose-metabolism
#18
Young Taek Oh, Hwa Young Kim, Eun Jin Kim, Junhyeok Go, Wontae Hwang, Hyoung Rae Kim, Dong Wook Kim, Sang Sun Yoon
Vibrio cholerae, a Gram-negative bacterium, is the causative agent of pandemic cholera. Previous studies have shown that the survival of the seventh pandemic El Tor biotype V. cholerae strain N16961 requires production of acetoin in a glucose-rich environment. The production of acetoin, a neutral fermentation end-product, allows V. cholerae to metabolize glucose without a pH drop, which is mediated by the production of organic acid. This finding suggests that inhibition of acetoin fermentation can result in V...
2016: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/27875634/the-stringent-response-plays-a-key-role-in-bacillus-subtilis-survival-of-fatty-acid-starvation
#19
André A Pulschen, Diego E Sastre, Federico Machinandiarena, Agostina Crotta Asis, Daniela Albanesi, Diego de Mendoza, Frederico J Gueiros-Filho
The stringent response is a universal adaptive mechanism to protect bacteria from nutritional and environmental stresses. The role of the stringent response during lipid starvation has been studied only in Gram-negative bacteria. Here, we report that the stringent response also plays a crucial role in the adaptation of the model Gram-positive Bacillus subtilis to fatty acid starvation. B. subtilis lacking all three (p)ppGpp-synthetases (RelBs , RelP and RelQ) or bearing a RelBs variant that no longer synthesizes (p)ppGpp suffer extreme loss of viability on lipid starvation...
November 22, 2016: Molecular Microbiology
https://www.readbyqxmd.com/read/27819280/cationic-bactericidal-peptide-1018-does-not-specifically-target-the-stringent-response-alarmone-p-ppgpp
#20
Liis Andresen, Tanel Tenson, Vasili Hauryliuk
The bacterial stringent response is a key regulator of bacterial virulence, biofilm formation and antibiotic tolerance, and is a promising target for the development of new antibacterial compounds. The intracellular nucleotide (p)ppGpp acts as a messenger orchestrating the stringent response. A synthetic peptide 1018 was recently proposed to specifically disrupt biofilms by inhibiting the stringent response via direct interaction with (p)ppGpp (de la Fuente-Núñez et al. (2014) PLoS Pathogens). We have interrogated the specificity of the proposed molecular mechanism...
November 7, 2016: Scientific Reports
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