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  Antigen 85C Inhibition Restricts Mycobacterium tuberculosis Growth through Disruption of Cord Factor Biosynthesis

Warrier, T., Tropis, M., Werngren, J., Diehl, A., Gengenbacher, M., Schlegel, B., et al. (2012). Antigen 85C Inhibition Restricts Mycobacterium tuberculosis Growth through Disruption of Cord Factor Biosynthesis. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 56(4), 1735-1743. doi:10.1128/AAC.05742-11.

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Datensatz-Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-BE02-2 Versions-Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-BE03-F
Genre: Zeitschriftenartikel
Alternativer Titel : Antimicrob. Agents Chemother.

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Antimicr_Agents_Chemother_2012_56_1735.pdf (Verlagsversion), 2MB
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 Urheber:
Warrier, Thulasi1, Autor              
Tropis, Marielle, Autor
Werngren, Jim, Autor
Diehl, Anne, Autor
Gengenbacher, Martin1, Autor              
Schlegel, Brigitte, Autor
Schade, Markus, Autor
Oschkinat, Hartmut, Autor
Daffe, Mamadou, Autor
Hoffner, Sven, Autor
Eddine, Ali Nasser1, Autor              
Kaufmann, Stefan H. E.1, Autor              
Affiliations:
1Department of Immunology, Max Planck Institute for Infection Biology, Max Planck Society, escidoc:1664146              

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 Zusammenfassung: The antigen 85 (Ag85) protein family, consisting of Ag85A, -B, and -C, is vital for Mycobacterium tuberculosis due to its role in cell envelope biogenesis. The mycoloyl transferase activity of these proteins generates trehalose dimycolate (TDM), an envelope lipid essential for M. tuberculosis virulence, and cell wall arabinogalactan-linked mycolic acids. Inhibition of these enzymes through substrate analogs hinders growth of mycobacteria, but a link to mycolic acid synthesis has not been established. In this study, we characterized a novel inhibitor of Ag85C, 2-amino-6-propyl-4,5,6,7-tetrahydro-l-benzothiophene-3-carbonitrile (I3-AG85). I3-AG85 was isolated from a panel of four inhibitors that exhibited structure- and dose-dependent inhibition of M. tuberculosis division in broth culture. I3-AG85 also inhibited M. tuberculosis survival in infected primary macrophages. Importantly, it displayed an identical MIC against the drug-susceptible H37Rv reference strain and a panel of extensively drug-resistant/multidrug-resistant M. tuberculosis strains. Nuclear magnetic resonance analysis indicated binding of I3-AG85 to Ag85C, similar to its binding to the artificial substrate octylthioglucoside. Quantification of mycolic acid-linked lipids of the M. tuberculosis envelope showed a specific blockade of TDM synthesis. This was accompanied by accumulation of trehalose monomycolate, while the overall mycolic acid abundance remained unchanged. Inhibition of Ag85C activity also disrupted the integrity of the M. tuberculosis envelope. I3-AG85 inhibited the division of and reduced TDM synthesis in an M. tuberculosis strain deficient in Ag85C. Our results indicate that Ag85 proteins are promising targets for novel antimycobacterial drug design.

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Sprache(n): eng - Englisch
 Datum: 2012-04
 Publikationsstatus: Im Druck publiziert
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: eDoc: 610055
ISI: 000301898500009
DOI: 10.1128/AAC.05742-11
 Art des Abschluß: -

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Titel: ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
  Alternativer Titel : Antimicrob. Agents Chemother.
Genre der Quelle: Zeitschrift
 Urheber:
Affiliations:
Ort, Verlag, Ausgabe: WASHINGTON : AMER SOC MICROBIOLOGY
Seiten: - Band / Heft: 56 (4) Artikelnummer: - Start- / Endseite: 1735 - 1743 Identifikator: ISSN: 0066-4804