title: Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane.
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.
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Grzegorzewicz
authors.forename: Ha
authors.initials: H
authors.lastname: Pham
authors.forename: Vijay A K B
authors.initials: VA
authors.lastname: Gundi
authors.forename: Michael S
authors.initials: MS
authors.lastname: Scherman
authors.forename: Elton J
authors.initials: EJ
authors.lastname: North
authors.forename: Tamara
authors.initials: T
authors.lastname: Hess
authors.forename: Victoria
authors.initials: V
authors.lastname: Jones
authors.forename: Veronica
authors.initials: V
authors.lastname: Gruppo
authors.forename: Sarah E M
authors.initials: SE
authors.lastname: Born
authors.forename: Jana
authors.initials: J
authors.lastname: Korduláková
authors.forename: Sivagami Sundaram
authors.initials: SS
authors.lastname: Chavadi
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Lenaerts
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
authors.forename: Michael R
authors.initials: MR
authors.lastname: McNeil
authors.forename: Mary
authors.initials: M
authors.lastname: Jackson
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D003311:Cord Factors; D004353:Drug Evaluation, Preclinical / Q000379:methods; D024881:Drug Resistance, Bacterial; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009171:Mycolic Acids / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries; D014199:Trehalose / Q000378:metabolism
chemical_list: C572246:1-(2-adamantyl)-3-(2,3,4-trifluorophenyl)urea; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003311:Cord Factors; D026901:Membrane Transport Proteins; D009171:Mycolic Acids; D010671:Phenylurea Compounds; D054852:Small Molecule Libraries; C021099:trehalose monomycolate; D014199:Trehalose; D000218:Adamantane