Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane

被引：2

作者：

Grzegorzewicz, Anna E. ^{[1
]}

Ha Pham ^{[1
]}

Gundi, Vijay A. K. B. ^{[1
]}

Scherman, Michael S. ^{[1
]}

North, Elton J. ^{[2
]}

Hess, Tamara ^{[1
]}

Jones, Victoria ^{[1
]}

Gruppo, Veronica ^{[1
]}

Born, Sarah E. M. ^{[1
]}

Kordulakova, Jana ^{[3
]}

Chavadi, Sivagami Sundaram ^{[1
]}

Morisseau, Christophe ^{[4
,5
]}

Lenaerts, Anne J. ^{[1
]}

Lee, Richard E. ^{[2
]}

McNeil, Michael R. ^{[1
]}

Jackson, Mary ^{[1
]}

机构：

[1] Colorado State Univ, Dept Microbiol Immunol & Pathol, Mycobacteria Res Labs, Ft Collins, CO 80523 USA

[2] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, Memphis, TN 38105 USA

[3] Comenius Univ, Fac Nat Sci, Dept Biochem, Bratislava, Slovakia

[4] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA

[5] Univ Calif Davis, Ctr Canc, Davis, CA 95616 USA

来源：

NATURE CHEMICAL BIOLOGY | 2012年 / 8卷 / 04期

关键词：

CELL-WALL; OUTER-MEMBRANE; BIOSYNTHESIS; TREHALOSE; VIRULENCE; DRUG; PERMEABILITY; REDUCTASE; PATHWAY; ANTIGEN;

D O I：

10.1038/NCHEMBIO.794

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：334 / 341

页数：8

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