1. Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane.
- Author
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Grzegorzewicz AE, Pham H, Gundi VA, Scherman MS, North EJ, Hess T, Jones V, Gruppo V, Born SE, Korduláková J, Chavadi SS, Morisseau C, Lenaerts AJ, Lee RE, McNeil MR, and Jackson M
- Subjects
- Adamantane chemistry, Adamantane pharmacology, Anti-Bacterial Agents pharmacokinetics, Bacterial Proteins metabolism, Biological Transport drug effects, Cell Membrane drug effects, Cord Factors, Drug Evaluation, Preclinical methods, Drug Resistance, Bacterial, Membrane Transport Proteins genetics, Membrane Transport Proteins metabolism, Microbial Sensitivity Tests, Mutation, Mycobacterium tuberculosis genetics, Mycobacterium tuberculosis metabolism, Phenylurea Compounds chemistry, Small Molecule Libraries, Trehalose metabolism, Adamantane analogs & derivatives, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Cell Membrane metabolism, Mycobacterium tuberculosis drug effects, Mycolic Acids metabolism, Phenylurea Compounds pharmacology
- Abstract
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.
- Published
- 2012
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