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https://doi.org/10.1128/AAC.05742-11
Title: | Antigen 85C inhibition restricts Mycobacterium tuberculosis growth through disruption of cord factor biosynthesis | Authors: | Warrier, T Tropis, M Werngren, J Diehl, A Gengenbacher, M Schlegel, B Schade, M Oschkinat, H Daffe, M Hoffner, S Eddine, A.N Kaufmann, S.H.E |
Keywords: | 2 amino 6 propyl 4,5,6,7 tetrahydro 1 benzothiophene 3 carbonitrile antigen antigen 85c cord factor protein inhibitor unclassified drug animal cell antigen binding antigen purification article bacterial growth bacterial membrane bacterial survival bacterium culture broth dilution controlled study lipogenesis macrophage membrane damage mouse Mycobacterium tuberculosis nonhuman nuclear magnetic resonance priority journal Acyltransferases Animals Antigens, Bacterial Bone Marrow Cells Cell Membrane Permeability Cell Survival Cord Factors Culture Media Drug Resistance, Bacterial Drug Resistance, Multiple, Bacterial Female Lipids Macrophages Magnetic Resonance Spectroscopy Mice Mice, Inbred C57BL Mycobacterium tuberculosis Oxazines Recombinant Proteins Thioglucosides Uracil Xanthenes |
Issue Date: | 2012 | Citation: | Warrier, T, Tropis, M, Werngren, J, Diehl, A, Gengenbacher, M, Schlegel, B, Schade, M, Oschkinat, H, Daffe, M, Hoffner, S, Eddine, A.N, Kaufmann, S.H.E (2012). Antigen 85C inhibition restricts Mycobacterium tuberculosis growth through disruption of cord factor biosynthesis. Antimicrobial Agents and Chemotherapy 56 (4) : 1735-1743. ScholarBank@NUS Repository. https://doi.org/10.1128/AAC.05742-11 | Rights: | Attribution 4.0 International | 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-1- 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. Copyright © 2012, American Society for Microbiology. All Rights Reserved. | Source Title: | Antimicrobial Agents and Chemotherapy | URI: | https://scholarbank.nus.edu.sg/handle/10635/180840 | ISSN: | 0066-4804 | DOI: | 10.1128/AAC.05742-11 | Rights: | Attribution 4.0 International |
Appears in Collections: | Staff Publications Elements |
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