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Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane

2012; Nature Portfolio; Volume: 8; Issue: 4 Linguagem: Inglês

10.1038/nchembio.794

1552-4469

Anna E. Grzegorzewicz, Hà Phạm, Vijay A.K.B. Gundi, Michaël Scherman, E. Jeffrey North, Tamara Hess, Victoria Jones, Veronica Gruppo, Sarah E. M. Born, Jana Korduláková, Sivagami Sundaram Chavadi, Christophe Morisseau, Anne J. Lenaerts, Richard Lee, Michael McNeil, Mary Jackson,

Pharmacological Effects of Natural Compounds

An adamantyl urea derivative identified as a potent bactericidal compound against Mycobacterium species and multidrug-resistant M. tuberculosis targets a late step in biogenesis of very-long-chain cell wall–bound mycolic acids—by inhibiting the transport of the fatty acids across the bacterial plasma membrane. 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.