TY - JOUR
T1 - Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane
AU - Grzegorzewicz, Anna E.
AU - Pham, Ha
AU - Gundi, Vijay A.K.B.
AU - Scherman, Michael S.
AU - North, Elton J.
AU - Hess, Tamara
AU - Jones, Victoria
AU - Gruppo, Veronica
AU - Born, Sarah E.M.
AU - Korduláková, Jana
AU - Chavadi, Sivagami Sundaram
AU - Morisseau, Christophe
AU - Lenaerts, Anne J.
AU - Lee, Richard E.
AU - McNeil, Michael R.
AU - Jackson, Mary
N1 - Funding Information:
This work was supported by the NIAID and NIH grants AI085992, AI063054 and AI057836; the American Lebanese Syrian Associated Charities; and the Slovak Research and Development Agency under contract no. APVV-0441-10. We thank R. Dhiman for helpful scientific discussions and D. Dick for LC/MS analyses. Purified recombinant FbpC (Ag85C) was kindly provided by K. Dobos (Colorado State University).
PY - 2012/4
Y1 - 2012/4
N2 - New chemotherapeutics active against multidrug-resistant Mycobacterium tuberculosis are urgently needed. We report on the identification of an adamantyl urea compound that shows potent bactericidal activity against M. tuberculosis and a unique mode of action, namely the abolition of the translocation of mycolic acids from the cytoplasm, where they are synthesized to the periplasmic side of the plasma membrane and are in turn transferred onto cell wall arabinogalactan or used in the formation of virulence-associated, outer membrane, trehalose-containing glycolipids. Whole-genome sequencing of spontaneous-resistant mutants of M. tuberculosis selected in vitro followed by genetic validation experiments revealed that our prototype inhibitor targets the inner membrane transporter MmpL3. Conditional gene expression of mmpL3 in mycobacteria and analysis of inhibitor-treated cells validate MmpL3 as essential for mycobacterial growth and support the involvement of this transporter in the translocation of trehalose monomycolate across the plasma membrane.
AB - New chemotherapeutics active against multidrug-resistant Mycobacterium tuberculosis are urgently needed. We report on the identification of an adamantyl urea compound that shows potent bactericidal activity against M. tuberculosis and a unique mode of action, namely the abolition of the translocation of mycolic acids from the cytoplasm, where they are synthesized to the periplasmic side of the plasma membrane and are in turn transferred onto cell wall arabinogalactan or used in the formation of virulence-associated, outer membrane, trehalose-containing glycolipids. Whole-genome sequencing of spontaneous-resistant mutants of M. tuberculosis selected in vitro followed by genetic validation experiments revealed that our prototype inhibitor targets the inner membrane transporter MmpL3. Conditional gene expression of mmpL3 in mycobacteria and analysis of inhibitor-treated cells validate MmpL3 as essential for mycobacterial growth and support the involvement of this transporter in the translocation of trehalose monomycolate across the plasma membrane.
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U2 - 10.1038/nchembio.794
DO - 10.1038/nchembio.794
M3 - Article
C2 - 22344175
AN - SCOPUS:84858677107
SN - 1552-4450
VL - 8
SP - 334
EP - 341
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 4
ER -
