Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane

被引：0
作者：
Anna E Grzegorzewicz
Ha Pham
Vijay A K B Gundi
Michael S Scherman
Elton J North
Tamara Hess
Victoria Jones
Veronica Gruppo
Sarah E M Born
Jana Korduláková
Sivagami Sundaram Chavadi
Christophe Morisseau
Anne J Lenaerts
Richard E Lee
Michael R McNeil
Mary Jackson
机构：
[1] Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO
[2] Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN
[3] Department of Biochemistry, Faculty of Natural Sciences, Comenius University, Bratislava
[4] Department of Entomology, University of California-Davis, Davis, CA
[5] University of California, Davis Cancer Center, Davis, CA
来源：
Nature Chemical Biology | 2012年 / 8卷 / 4期
基金：
英国科研创新办公室; 美国国家卫生研究院;
关键词：
D O I：
10.1038/nchembio.794
中图分类号：
学科分类号：
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. © 2012 Nature America, Inc. All rights reserved.
引用
收藏
页码：334 / 341
页数：7
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