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https://www.readbyqxmd.com/read/28438933/pyrazinoic-acid-inhibits-a-bifunctional-enzyme-in-mycobacterium-tuberculosis
#1
Moses Njire, Na Wang, Bangxing Wang, Yaoju Tan, Xingshan Cai, Yanwen Liu, Julius Mugweru, Jintao Guo, H M Adnan Hameed, Shouyong Tan, Jianxiong Liu, Wing Wai Yew, Eric Nuermberger, Gyanu Lamichhane, Jinsong Liu, Tianyu Zhang
Pyrazinamide (PZA), an indispensable component of modern tuberculosis treatment, acts as a key sterilizing drug. While the mechanism of activation of this prodrug by Mycobacterium tuberculosis into pyrazinoic acid (POA) has been extensively studied, not all molecular determinants that confer resistance to this mysterious drug have been identified. Here, we report a new PZA resistance determinant: Asp67Asn substitution in Rv2783 confers M. tuberculosis resistance to PZA. Expression of the mutant but not the wild-type allele in M...
April 24, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28396544/synthetic-p-ppgpp-analogue-inhibitor-of-stringent-response-in-mycobacteria
#2
Kirtimaan Syal, Kelly Flentie, Neerupma Bhardwaj, Krishnagopal Maiti, Narayanaswamy Jayaraman, Christina L Stallings, Dipankar Chatterji
Bacteria elicit an adaptive response against hostile conditions such as starvation and other kind of stresses. Their ability to survive such conditions depends on, in part, stringent response pathways. (p)ppGpp, considered to be the master regulator of stringent response, is a novel target for inhibiting the survival of the bacteria. In mycobacteria, the (p)ppGpp synthetase activity of bifunctional Rel is critical for its stress response and persistence inside the host. Our aim was to design an inhibitor of (p)ppGpp synthesis, follow efficiency through enzyme kinetics, and assess its phenotypic effects in mycobacteria...
April 10, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28388876/transcriptomic-buffering-of-cryptic-genetic-variation-contributes-to-meningococcal-virulence
#3
Biju Joseph Ampattu, Laura Hagmann, Chunguang Liang, Marcus Dittrich, Andreas Schlüter, Jochen Blom, Elizaveta Krol, Alexander Goesmann, Anke Becker, Thomas Dandekar, Tobias Müller, Christoph Schoen
BACKGROUND: Commensal bacteria like Neisseria meningitidis sometimes cause serious disease. However, genomic comparison of hyperinvasive and apathogenic lineages did not reveal unambiguous hints towards indispensable virulence factors. Here, in a systems biological approach we compared gene expression of the invasive strain MC58 and the carriage strain α522 under different ex vivo conditions mimicking commensal and virulence compartments to assess the strain-specific impact of gene regulation on meningococcal virulence...
April 7, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28320944/negative-allosteric-regulation-of-enterococcus-faecalis-small-alarmone-synthetase-relq-by-single-stranded-rna
#4
Jelena Beljantseva, Pavel Kudrin, Liis Andresen, Victoria Shingler, Gemma C Atkinson, Tanel Tenson, Vasili Hauryliuk
The alarmone nucleotides guanosine pentaphosphate (pppGpp) and tetraphosphate (ppGpp), collectively referred to as (p)ppGpp, are key regulators of bacterial growth, stress adaptation, pathogenicity, and antibiotic tolerance. We show that the tetrameric small alarmone synthetase (SAS) RelQ from the Gram-positive pathogen Enterococcus faecalis is a sequence-specific RNA-binding protein. RelQ's enzymatic and RNA binding activities are subject to intricate allosteric regulation. (p)ppGpp synthesis is potently inhibited by the binding of single-stranded RNA...
April 4, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28303404/phylogenetic-analysis-of-proteins-involved-in-the-stringent-response-in-plant-cells
#5
Doshun Ito, Yuta Ihara, Hidenori Nishihara, Shinji Masuda
The nucleotide (p)ppGpp is a second messenger that controls the stringent response in bacteria. The stringent response modifies expression of a large number of genes and metabolic processes and allows bacteria to survive under fluctuating environmental conditions. Recent genome sequencing analyses have revealed that genes responsible for the stringent response are also found in plants. These include (p)ppGpp synthases and hydrolases, RelA/SpoT homologs (RSHs), and the pppGpp-specific phosphatase GppA/Ppx. However, phylogenetic relationship between enzymes involved in bacterial and plant stringent responses is as yet generally unclear...
March 16, 2017: Journal of Plant Research
https://www.readbyqxmd.com/read/28265086/polyphosphate-granule-biogenesis-is-temporally-and-functionally-tied-to-cell-cycle-exit-during-starvation-in-pseudomonas-aeruginosa
#6
Lisa R Racki, Elitza I Tocheva, Michael G Dieterle, Meaghan C Sullivan, Grant J Jensen, Dianne K Newman
Polyphosphate (polyP) granule biogenesis is an ancient and ubiquitous starvation response in bacteria. Although the ability to make polyP is important for survival during quiescence and resistance to diverse environmental stresses, granule genesis is poorly understood. Using quantitative microscopy at high spatial and temporal resolution, we show that granule genesis in Pseudomonas aeruginosa is tightly organized under nitrogen starvation. Following nucleation as many microgranules throughout the nucleoid, polyP granules consolidate and become transiently spatially organized during cell cycle exit...
March 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28242673/bifunctional-enzyme-spot-is-involved-in-the-clarithromycin-tolerance-of-helicobacter-pylori-by-up-regulating-the-transporters-hp0939-hp1017-hp0497-and-hp0471
#7
Xiwen Geng, Wen Li, Zhenghong Chen, Sizhe Gao, Wei Hong, Xiaoran Ge, Guihua Hou, Zhekai Hu, Yabin Zhou, Beini Zeng, Wenjuan Li, Jihui Jia, Yundong Sun
Clarithromycin (CLA) is a commonly recommended drug for Helicobacter pylori eradication. However, the prevalence of CLA-resistant H. pylori is increasing. Although point mutations in the 23S ribosomal RNA (rRNA) are key factors for CLA resistance, other factors, including efflux pumps and regulation genes, are also involved in the CLA resistance of H. pylori Guanosine 3' -diphosphate 5' -triphosphate and guanosine 3', 5' -bispyrophosphate ((p)ppGpp), which are synthesized by the bifunctional enzyme SpoT in H...
February 27, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28228329/stringent-factor-and-proteolysis-control-of-sigma-factor-rpos-expression-in-vibrio-cholerae
#8
Philipp Wurm, Sarah Tutz, Beatrice Mutsam, Dina Vorkapic, Barbara Heyne, Claudia Grabner, Katharina Kleewein, Anja Halscheidt, Stefan Schild, Joachim Reidl
Vibrio cholerae can colonize the gastrointestinal track of humans and cause the disease cholera. During colonization, the alternative sigma factor, RpoS, controls a process known as "mucosal escape response," defining a specific spatial and temporal response and effecting chemotaxis and motility. In this report, the expression and proteolytic control of RpoS in V. cholerae was characterized. To date, aspects of proteolysis control, the involved components, and proteolysis regulation have not been addressed for RpoS in V...
April 2017: International Journal of Medical Microbiology: IJMM
https://www.readbyqxmd.com/read/28220595/guanosine-tetraphosphate-modulates-salicylic-acid-signaling-and-the-resistance-of-arabidopsis-thaliana-to-turnip-mosaic-virus
#9
Hela Abdelkefi, Matteo Sugliani, Ke Hang, Seddik Harchouni, Ludivine Soubigou-Taconnat, Sylvie Citerne, Gregory Mouille, Hatem Fakhfakh, Christophe Robaglia, Ben Field
Chloroplasts can act as key players in the perception and acclimation of plants to incoming environmental signals. A growing body of evidence indicates that chloroplasts play a critical role in plant immunity. Chloroplast function can be regulated by the nucleotides guanosine tetraphosphate and pentaphosphate ((p)ppGpp). In plants (p)ppGpp levels increase in response to abiotic stress and to plant hormones that are involved in abiotic and biotic stress signaling. Here we analyzed the transcriptome of Arabidopsis plants that over accumulate (p)ppGpp and unexpectedly found a decrease in the levels of a broad range of transcripts for plant defense and immunity...
February 21, 2017: Molecular Plant Pathology
https://www.readbyqxmd.com/read/28174313/atp-dependent-persister-formation-in-escherichia-coli
#10
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
#11
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 catalyzes conversion of 5'-terminal triphosphate to 5'-terminal monophosphate on RNAs. Although the C-terminal half (CTH), beyond residue approximately 500, of RNase E is dispensable for viability, deletion of the CTH 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...
April 15, 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
#12
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
#13
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
#14
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/subinhibitory-concentrations-of-bacteriostatic-antibiotics-induce-rela-dependent-and-rela-independent-tolerance-to-%C3%AE-lactams
#15
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...
April 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28067906/prophage-mediated-defence-against-viral-attack-and-viral-counter-defence
#16
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
#17
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
#18
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
#19
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
#20
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
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