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Article ; Online: Mycobacterium tuberculosis β-lactamase variant reduces sensitivity to ampicillin/avibactam in a zebrafish-Mycobacterium marinum model of tuberculosis.

van Alen, Ilona / Aguirre García, Mayra A / Maaskant, Janneke J / Kuijl, Coenraad P / Bitter, Wilbert / Meijer, Annemarie H / Ubbink, Marcellus

Scientific reports

2023 Volume 13, Issue 1, Page(s) 15406

Abstract: The β-lactamase of Mycobacterium tuberculosis, BlaC, hydrolyzes β-lactam antibiotics, hindering the use of these antibiotics for the treatment of tuberculosis. Inhibitors, such as avibactam, can reversibly inhibit the enzyme, allowing for the development ...

Abstract	The β-lactamase of Mycobacterium tuberculosis, BlaC, hydrolyzes β-lactam antibiotics, hindering the use of these antibiotics for the treatment of tuberculosis. Inhibitors, such as avibactam, can reversibly inhibit the enzyme, allowing for the development of combination therapies using both antibiotic and inhibitor. However, laboratory evolution studies using Escherichia coli resulted in the discovery of single amino acid variants of BlaC that reduce the sensitivity for inhibitors or show higher catalytic efficiency against antibiotics. Here, we tested these BlaC variants under more physiological conditions using the M. marinum infection model of zebrafish, which recapitulates hallmark features of tuberculosis, including the intracellular persistence of mycobacteria in macrophages and the induction of granuloma formation. To this end, the M. tuberculosis blaC gene was integrated into the chromosome of a blaC frameshift mutant of M. marinum. Subsequently, the resulting strains were used to infect zebrafish embryos in order to test the combinatorial effect of ampicillin and avibactam. The results show that embryos infected with an M. marinum strain producing BlaC show lower infection levels after treatment than untreated embryos. Additionally, BlaC K234R showed higher infection levels after treatment than those infected with bacteria producing the wild-type enzyme, demonstrating that the zebrafish host is less sensitive to the combinatorial therapy of β-lactam antibiotic and inhibitor. These findings are of interest for future development of combination therapies to treat tuberculosis.
MeSH term(s)	Animals ; Mycobacterium tuberculosis/genetics ; Zebrafish ; Mycobacterium marinum/genetics ; beta-Lactamases/genetics ; Tuberculosis/drug therapy ; Ampicillin ; Anti-Bacterial Agents ; Escherichia coli/genetics
Chemical Substances	avibactam (7352665165) ; beta-Lactamases (EC 3.5.2.6) ; Ampicillin (7C782967RD) ; Anti-Bacterial Agents
Language	English
Publishing date	2023-09-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-42152-8
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Article ; Online: Ectopic expression of cGAS in

Waanders, Lisette / van der Donk, Lieve E H / Ates, Louis S / Maaskant, Janneke / van Hamme, John L / Eldering, Eric / van Bruggen, Jaco A C / Rietveld, Joanne M / Bitter, Wilbert / Geijtenbeek, Teunis B H / Kuijl, Coenraad P

Journal for immunotherapy of cancer

2023 Volume 11, Issue 4

Abstract: Background: Interferon (IFN)-β induction via activation of the stimulator of interferon genes (STING) pathway has shown promising results in tumor models. STING is activated by cyclic dinucleotides such as cyclic GMP-AMP dinucleotides with ... ...

Abstract	Background: Interferon (IFN)-β induction via activation of the stimulator of interferon genes (STING) pathway has shown promising results in tumor models. STING is activated by cyclic dinucleotides such as cyclic GMP-AMP dinucleotides with phosphodiester linkages 2'-5' and 3'-5' (cGAMPs), that are produced by cyclic GMP-AMP synthetase (cGAS). However, delivery of STING pathway agonists to the tumor site is a challenge. Bacterial vaccine strains have the ability to specifically colonize hypoxic tumor tissues and could therefore be modified to overcome this challenge. Combining high STING-mediated IFN-β levels with the immunostimulatory properties of Methods: We have engineered Results: Expression of cGAS in Conclusion: S. typhimurium
MeSH term(s)	Humans ; Salmonella typhimurium/metabolism ; Ectopic Gene Expression ; Nucleotidyltransferases/genetics ; Nucleotidyltransferases/metabolism ; Macrophages/metabolism ; Interferon Type I ; Neoplasms/metabolism ; Dendritic Cells/metabolism ; Tumor Microenvironment
Chemical Substances	cyclic guanosine monophosphate-adenosine monophosphate ; Nucleotidyltransferases (EC 2.7.7.-) ; Interferon Type I
Language	English
Publishing date	2023-04-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2022-005839
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Article ; Online: Efficient genome editing in pathogenic mycobacteria using Streptococcus thermophilus CRISPR1-Cas9.

Meijers, Aniek S / Troost, Ran / Ummels, Roy / Maaskant, Janneke / Speer, Alexander / Nejentsev, Sergey / Bitter, Wilbert / Kuijl, Coenraad P

Tuberculosis (Edinburgh, Scotland)

2020 Volume 124, Page(s) 101983

Abstract: The ability to genetically engineer pathogenic mycobacteria has increased significantly over the last decades due to the generation of new molecular tools. Recently, the application of the Streptococcus pyogenes and the Streptococcus thermophilus CRISPR- ... ...

Abstract	The ability to genetically engineer pathogenic mycobacteria has increased significantly over the last decades due to the generation of new molecular tools. Recently, the application of the Streptococcus pyogenes and the Streptococcus thermophilus CRISPR-Cas9 systems in mycobacteria has enabled gene editing and efficient CRISPR interference-mediated transcriptional regulation. Here, we converted CRISPR interference into an efficient genome editing tool for mycobacteria. We demonstrate that the Streptococcus thermophilus CRISPR1-Cas9 (Sth1Cas9) is functional in Mycobacterium marinum and Mycobacterium tuberculosis, enabling highly efficient and precise DNA breaks and indel formation, without any off-target effects. In addition, with dual sgRNAs this system can be used to generate two indels simultaneously or to create specific deletions. The ability to use the power of the CRISPR-Cas9-mediated gene editing toolbox in M. tuberculosis with a single step will accelerate research into this deadly pathogen.
MeSH term(s)	Antitubercular Agents/pharmacology ; Bacterial Proteins/genetics ; CRISPR-Associated Protein 9/genetics ; CRISPR-Associated Protein 9/metabolism ; CRISPR-Cas Systems ; Catalase/genetics ; Clustered Regularly Interspaced Short Palindromic Repeats ; Drug Resistance, Bacterial/drug effects ; Gene Deletion ; Gene Editing ; Gene Expression Regulation, Bacterial ; INDEL Mutation ; Isoniazid/pharmacology ; Mycobacterium marinum/genetics ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/genetics ; Mycobacterium tuberculosis/growth & development ; RNA, Guide, CRISPR-Cas Systems/genetics ; Streptococcus thermophilus/enzymology ; Streptococcus thermophilus/genetics
Chemical Substances	Antitubercular Agents ; Bacterial Proteins ; RNA, Guide, CRISPR-Cas Systems ; Catalase (EC 1.11.1.6) ; katG protein, Mycobacterium tuberculosis (EC 1.11.1.6) ; CRISPR-Associated Protein 9 (EC 3.1.-) ; Isoniazid (V83O1VOZ8L)
Language	English
Publishing date	2020-08-12
Publishing country	Scotland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2046804-0
ISSN	1873-281X ; 1472-9792
ISSN (online)	1873-281X
ISSN	1472-9792
DOI	10.1016/j.tube.2020.101983
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Article ; Online: The anti-mycobacterial activity of the cytochrome bcc inhibitor Q203 can be enhanced by small-molecule inhibition of cytochrome bd.

Lu, Ping / Asseri, Amer H / Kremer, Martijn / Maaskant, Janneke / Ummels, Roy / Lill, Holger / Bald, Dirk

Scientific reports

2018 Volume 8, Issue 1, Page(s) 2625

Abstract: Mycobacterial energy metabolism currently attracts strong attention as new target space for development of anti-tuberculosis drugs. The imidazopyridine Q203 targets the cytochrome bcc complex of the respiratory chain, a key component in energy metabolism. ...

Abstract	Mycobacterial energy metabolism currently attracts strong attention as new target space for development of anti-tuberculosis drugs. The imidazopyridine Q203 targets the cytochrome bcc complex of the respiratory chain, a key component in energy metabolism. Q203 blocks growth of Mycobacterium tuberculosis at nanomolar concentrations, however, it fails to actually kill the bacteria, which may limit the clinical applicability of this candidate drug. In this report we show that inhibition of cytochrome bd, a parallel branch of the mycobacterial respiratory chain, by aurachin D invoked bactericidal activity of Q203. In biochemical assays using inverted membrane vesicles from Mycobacterium tuberculosis and Mycobacterium smegmatis we found that inhibition of respiratory chain activity by Q203 was incomplete, but could be enhanced by inactivation of cytochrome bd, either by genetic knock-out or by inhibition with aurachin D. These results indicate that simultaneously targeting the cytochrome bcc and the cytochrome bd branch of the mycobacterial respiratory chain may turn out as effective strategy for combating M. tuberculosis.
MeSH term(s)	Antitubercular Agents/pharmacology ; Cytochromes/antagonists & inhibitors ; Electron Transport/drug effects ; Imidazoles/pharmacology ; Mycobacterium smegmatis/drug effects ; Mycobacterium tuberculosis/drug effects ; Piperidines/pharmacology ; Pyridines/pharmacology ; Quinolones/pharmacology
Chemical Substances	6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl) imidazo(1,2-a)pyridine-3-carboxamide ; Antitubercular Agents ; Cytochromes ; Imidazoles ; Piperidines ; Pyridines ; Quinolones ; aurachin D (108354-13-8)
Language	English
Publishing date	2018-02-08
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-20989-8
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Article ; Online: Inorganic Phosphate Limitation Modulates Capsular Polysaccharide Composition in Mycobacteria.

van de Weerd, Robert / Boot, Maikel / Maaskant, Janneke / Sparrius, Marion / Verboom, Theo / van Leeuwen, Lisanne M / Burggraaf, Maroeska J / Paauw, Nanne J / Dainese, Elisa / Manganelli, Riccardo / Bitter, Wilbert / Appelmelk, Ben J / Geurtsen, Jeroen

The Journal of biological chemistry

2016 Volume 291, Issue 22, Page(s) 11787–11799

Abstract: Mycobacterium tuberculosis is protected by an unusual and highly impermeable cell envelope that is critically important for the successful colonization of the host. The outermost surface of this cell envelope is formed by capsular polysaccharides that ... ...

Abstract	Mycobacterium tuberculosis is protected by an unusual and highly impermeable cell envelope that is critically important for the successful colonization of the host. The outermost surface of this cell envelope is formed by capsular polysaccharides that play an important role in modulating the initial interactions once the bacillus enters the body. Although the bioenzymatic steps involved in the production of the capsular polysaccharides are emerging, information regarding the ability of the bacterium to modulate the composition of the capsule is still unknown. Here, we study the mechanisms involved in regulation of mycobacterial capsule biosynthesis using a high throughput screen for gene products involved in capsular α-glucan production. Utilizing this approach we identified a group of mutants that all carried mutations in the ATP-binding cassette phosphate transport locus pst These mutants collectively exhibited a strong overproduction of capsular polysaccharides, including α-glucan and arabinomannan, suggestive of a role for inorganic phosphate (Pi) metabolism in modulating capsular polysaccharide production. These findings were corroborated by the observation that growth under low Pi conditions as well as chemical activation of the stringent response induces capsule production in a number of mycobacterial species. This induction is, in part, dependent on σ factor E. Finally, we show that Mycobacterium marinum, a model organism for M. tuberculosis, encounters Pi stress during infection, which shows the relevance of our findings in vivo.
MeSH term(s)	Animals ; Bacterial Capsules/drug effects ; Bacterial Capsules/metabolism ; Embryo, Nonmammalian/drug effects ; Embryo, Nonmammalian/metabolism ; Embryo, Nonmammalian/microbiology ; Mycobacterium Infections, Nontuberculous/drug therapy ; Mycobacterium Infections, Nontuberculous/microbiology ; Mycobacterium marinum/drug effects ; Phosphates/pharmacology ; Polysaccharides/metabolism ; Zebrafish
Chemical Substances	Phosphates ; Polysaccharides
Language	English
Publishing date	2016-04-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M116.722454
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Article ; Online: Pyrazinoic acid decreases the proton motive force, respiratory ATP synthesis activity, and cellular ATP levels.

Lu, Ping / Haagsma, Anna C / Pham, Hoang / Maaskant, Janneke J / Mol, Selena / Lill, Holger / Bald, Dirk

Antimicrobial agents and chemotherapy

2011 Volume 55, Issue 11, Page(s) 5354–5357

Abstract: Pyrazinoic acid, the active form of the first-line antituberculosis drug pyrazinamide, decreased the proton motive force and respiratory ATP synthesis rates in subcellular mycobacterial membrane assays. Pyrazinoic acid also significantly lowered cellular ...

Abstract	Pyrazinoic acid, the active form of the first-line antituberculosis drug pyrazinamide, decreased the proton motive force and respiratory ATP synthesis rates in subcellular mycobacterial membrane assays. Pyrazinoic acid also significantly lowered cellular ATP levels in Mycobacterium bovis BCG. These results indicate that the predominant mechanism of killing by this drug may operate by depletion of cellular ATP reserves.
MeSH term(s)	Adenosine Triphosphate/biosynthesis ; Adenosine Triphosphate/metabolism ; Antitubercular Agents/pharmacology ; Cell Membrane/drug effects ; Cell Membrane/metabolism ; Mycobacterium bovis/drug effects ; Mycobacterium bovis/metabolism ; Proton-Motive Force/drug effects ; Pyrazinamide/analogs & derivatives ; Pyrazinamide/pharmacology
Chemical Substances	Antitubercular Agents ; Pyrazinamide (2KNI5N06TI) ; pyrazinoic acid (2WB23298SP) ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2011-08-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.00507-11
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Article ; Online: A murine monoclonal antibody to glycogen: characterization of epitope-fine specificity by saturation transfer difference (STD) NMR spectroscopy and its use in mycobacterial capsular α-glucan research.

van de Weerd, Robert / Berbís, M Alvaro / Sparrius, Marrion / Maaskant, Janneke J / Boot, Maikel / Paauw, Nanne J / de Vries, Nadine / Boon, Louis / Baba, Otto / Cañada, F Javier / Geurtsen, Jeroen / Jiménez-Barbero, Jesús / Appelmelk, Ben J

Chembiochem : a European journal of chemical biology

2015 Volume 16, Issue 6, Page(s) 977–989

Abstract: Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is a major pathogen responsible for 1.5 million deaths annually. This bacterium is characterized by a highly unusual and impermeable cell envelope, which plays a key role in ... ...

Abstract	Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is a major pathogen responsible for 1.5 million deaths annually. This bacterium is characterized by a highly unusual and impermeable cell envelope, which plays a key role in mycobacterial survival and virulence. Although many studies have focused on the composition and functioning of the mycobacterial cell envelope, the capsular α-glucan has received relatively minor attention. Here we show that a murine monoclonal antibody (Mab) directed against glycogen cross-reacts with mycobacterial α-glucans, polymers of α(1-4)-linked glucose residues with α(1-6)-branch points. We identified the Mab epitope specificity by saturation transfer difference NMR and show that the α(1-4)-linked glucose residues are important in glucan-Mab interaction. The minimal epitope is formed by (linear) maltotriose. Notably, a Mycobacterium mutant lacking the branching enzyme GlgB does not react with the Mab; this suggests that the α(1-6)-branches form part of the epitope. These seemingly conflicting data can be explained by the fact that in the mutant the linear form of the α-glucan (amylose) is insoluble. This Mab was subsequently used to develop several techniques helpful in capsular α-glucan research. By using a capsular glucan-screening methodology based on this Mab we were able to identify several unknown genes involved in capsular α-glucan biogenesis. Additionally, we developed two methods for the detection of capsular α-glucan levels. This study therefore opens new ways to study capsular α-glucan and to identify possible targets for further research.
MeSH term(s)	Animals ; Antibodies, Monoclonal/immunology ; Antibody Specificity ; Bacterial Capsules/metabolism ; Cell Wall/metabolism ; DNA Transposable Elements/genetics ; Epitopes/immunology ; Glycogen/biosynthesis ; Glycogen/chemistry ; Glycogen/immunology ; Glycogen/metabolism ; Magnetic Resonance Spectroscopy ; Mice ; Mutation ; Mycobacterium/cytology ; Mycobacterium/metabolism ; Oligosaccharides/chemistry
Chemical Substances	Antibodies, Monoclonal ; DNA Transposable Elements ; Epitopes ; Oligosaccharides ; Glycogen (9005-79-2)
Language	English
Publishing date	2015-04-13
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2020469-3
ISSN	1439-7633 ; 1439-4227
ISSN (online)	1439-7633
ISSN	1439-4227
DOI	10.1002/cbic.201402713
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Article: A truncated lipoglycan from mycobacteria with altered immunological properties

Birch, Helen L / Alderwick, Luke J / Appelmelk, Ben J / Maaskant, Janneke / Bhatt, Apoorva / Singh, Albel / Nigou, Jerome / Eggeling, Lothar / Geurtsen, Jeroen / Besra, Gurdyal S

Proceedings of the National Academy of Sciences of the United States of America. 2010 Feb. 9, v. 107, no. 6

2010

Abstract: Maintenance of cell-wall integrity in Mycobacterium tuberculosis is essential and is the target of several antitubercular drugs. For example, ethambutol targets arabinogalactan and lipoarabinomannan (LAM) biosynthesis through the inhibition of several ... ...

Abstract	Maintenance of cell-wall integrity in Mycobacterium tuberculosis is essential and is the target of several antitubercular drugs. For example, ethambutol targets arabinogalactan and lipoarabinomannan (LAM) biosynthesis through the inhibition of several arabinofuranosyltransferases. Apart from their role in cell-wall integrity, mycobacterial LAMs also exhibit important immunomodulatory activities. Here we report the isolation and detailed structural characterization of a unique LAM molecule derived from Mycobacterium smegmatis deficient in the arabinofuranosyltransferase AftC (AftC-LAM). This mutant LAM expresses a severely truncated arabinan domain completely devoid of 3,5-Araf-branching residues, revealing an intrinsic involvement of AftC in the biosynthesis of LAM. Furthermore, we found that ethambutol efficiently inhibits biosynthesis of the AftC-LAM arabinan core, unambiguously demonstrating the involvement of the arabinofuranosyltransferase EmbC in early stages of LAM-arabinan biosynthesis. Finally, we demonstrate that AftC-LAM exhibits an enhanced proinflammatory activity, which is due to its ability to activate Toll-like receptor 2 (TLR2). Overall, our efforts further describe the mechanism of action of an important antitubercular drug, ethambutol, and demonstrate a role for specific arabinofuranosyltransferases in LAM biosynthesis. In addition, the availability of sufficient amounts of chemically defined wild-type and isogenic truncated LAMs paves the way for further investigations of the structure-function relationship of TLR2 activation by mycobacterial lipoglycans.
Keywords	Mycobacterium smegmatis ; Mycobacterium tuberculosis ; Toll-like receptor 2 ; arabinogalactans ; biosynthesis ; drugs ; immunomodulation ; mechanism of action ; mutants ; structure-activity relationships
Language	English
Dates of publication	2010-0209
Size	p. 2634-2639.
Publishing place	National Academy of Sciences
Document type	Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0915082107
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Article ; Online: Cyanovirin-N inhibits mannose-dependent Mycobacterium-C-type lectin interactions but does not protect against murine tuberculosis.

Driessen, Nicole N / Boshoff, Helena I M / Maaskant, Janneke J / Gilissen, Sebastiaan A C / Vink, Simone / van der Sar, Astrid M / Vandenbroucke-Grauls, Christina M J E / Bewley, Carole A / Appelmelk, Ben J / Geurtsen, Jeroen

Journal of immunology (Baltimore, Md. : 1950)

2012 Volume 189, Issue 7, Page(s) 3585–3592

Abstract: Cyanovirin-N (CV-N) is a mannose-binding lectin that inhibits HIV-1 infection by blocking mannose-dependent target cell entry via C-type lectins. Like HIV-1, Mycobacterium tuberculosis expresses mannosylated surface structures and exploits C-type lectins ...

Abstract	Cyanovirin-N (CV-N) is a mannose-binding lectin that inhibits HIV-1 infection by blocking mannose-dependent target cell entry via C-type lectins. Like HIV-1, Mycobacterium tuberculosis expresses mannosylated surface structures and exploits C-type lectins to gain cell access. In this study, we investigated whether CV-N, like HIV-1, can inhibit M. tuberculosis infection. We found that CV-N specifically interacted with mycobacteria by binding to the mannose-capped lipoglycan lipoarabinomannan. Furthermore, CV-N competed with the C-type lectins DC-SIGN and mannose receptor for ligand binding and inhibited the binding of M. tuberculosis to dendritic cells but, unexpectedly, not to macrophages. Subsequent in vivo infection experiments in a mouse model demonstrated that, despite its activity, CV-N did not inhibit or delay M. tuberculosis infection. This outcome argues against a critical role for mannose-dependent C-type lectin interactions during the initial stages of murine M. tuberculosis infection and suggests that, depending on the circumstances, M. tuberculosis can productively infect cells using different modes of entry.
MeSH term(s)	Animals ; Bacterial Proteins/administration & dosage ; Bacterial Proteins/physiology ; Carrier Proteins/administration & dosage ; Carrier Proteins/physiology ; Cell Line ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Dendritic Cells/microbiology ; Disease Models, Animal ; Humans ; Lectins, C-Type/antagonists & inhibitors ; Lectins, C-Type/metabolism ; Macrophages/immunology ; Macrophages/metabolism ; Macrophages/microbiology ; Mannose/metabolism ; Mannose/physiology ; Mice ; Mice, Inbred C57BL ; Monocytes/immunology ; Monocytes/metabolism ; Monocytes/microbiology ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/immunology ; Mycobacterium tuberculosis/metabolism ; Protein Binding/drug effects ; Protein Binding/immunology ; Treatment Outcome ; Tuberculosis/immunology ; Tuberculosis/microbiology ; Tuberculosis/prevention & control
Chemical Substances	Bacterial Proteins ; Carrier Proteins ; Lectins, C-Type ; cyanovirin N (184539-38-6) ; Mannose (PHA4727WTP)
Language	English
Publishing date	2012-08-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1102408
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Article ; Online: Structure and function of RNase AS, a polyadenylate-specific exoribonuclease affecting mycobacterial virulence in vivo.

Romano, Maria / van de Weerd, Robert / Brouwer, Femke C C / Roviello, Giovanni N / Lacroix, Ruben / Sparrius, Marion / van den Brink-van Stempvoort, Gunny / Maaskant, Janneke J / van der Sar, Astrid M / Appelmelk, Ben J / Geurtsen, Jeroen J / Berisio, Rita

Structure (London, England : 1993)

2014 Volume 22, Issue 5, Page(s) 719–730

Abstract: The cell-envelope of Mycobacterium tuberculosis plays a key role in bacterial virulence and antibiotic resistance. Little is known about the molecular mechanisms of regulation of cell-envelope formation. Here, we elucidate functional and structural ... ...

Abstract	The cell-envelope of Mycobacterium tuberculosis plays a key role in bacterial virulence and antibiotic resistance. Little is known about the molecular mechanisms of regulation of cell-envelope formation. Here, we elucidate functional and structural properties of RNase AS, which modulates M. tuberculosis cell-envelope properties and strongly impacts bacterial virulence in vivo. The structure of RNase AS reveals a resemblance to RNase T from Escherichia coli, an RNase of the DEDD family involved in RNA maturation. We show that RNase AS acts as a 3'-5'-exoribonuclease that specifically hydrolyzes adenylate-containing RNA sequences. Also, crystal structures of complexes with AMP and UMP reveal the structural basis for the observed enzyme specificity. Notably, RNase AS shows a mechanism of substrate recruitment, based on the recognition of the hydrogen bond donor NH2 group of adenine. Our work opens a field for the design of drugs able to reduce bacterial virulence in vivo.
MeSH term(s)	Adenine ; Adenosine Monophosphate/chemistry ; Adenosine Monophosphate/metabolism ; Animals ; Bacterial Proteins/chemistry ; Bacterial Proteins/metabolism ; Crystallography, X-Ray ; Embryo, Nonmammalian/microbiology ; Exoribonucleases/chemistry ; Gene Knockout Techniques ; Hydrogen Bonding ; Models, Molecular ; Mutation ; Mycobacterium marinum/genetics ; Mycobacterium marinum/pathogenicity ; Mycobacterium tuberculosis/enzymology ; Mycobacterium tuberculosis/pathogenicity ; Poly A/metabolism ; Protein Multimerization ; Ribonucleases/chemistry ; Ribonucleases/genetics ; Ribonucleases/metabolism ; Substrate Specificity ; Uridine Monophosphate/chemistry ; Uridine Monophosphate/metabolism ; Zebrafish/embryology ; Zebrafish/microbiology
Chemical Substances	Bacterial Proteins ; Poly A (24937-83-5) ; Adenosine Monophosphate (415SHH325A) ; Uridine Monophosphate (E2OU15WN0N) ; Exoribonucleases (EC 3.1.-) ; Ribonucleases (EC 3.1.-) ; exoribonuclease T (EC 3.1.13.-) ; Adenine (JAC85A2161)
Language	English
Publishing date	2014-05-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2014.01.014
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