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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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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-BE02-2 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-000E-BE03-F
Genre: Journal Article
Alternative Title : Antimicrob. Agents Chemother.

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

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 Abstract: 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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Language(s): eng - English
 Dates: 2012-04
 Publication Status: Published in print
 Pages: -
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 Rev. Method: Peer
 Identifiers: eDoc: 610055
ISI: 000301898500009
DOI: 10.1128/AAC.05742-11
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Title: ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
  Alternative Title : Antimicrob. Agents Chemother.
Source Genre: Journal
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Publ. Info: WASHINGTON : AMER SOC MICROBIOLOGY
Pages: - Volume / Issue: 56 (4) Sequence Number: - Start / End Page: 1735 - 1743 Identifier: ISSN: 0066-4804