2012
DOI: 10.1038/nchembio.794
|View full text |Cite
|
Sign up to set email alerts
|

Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane

Abstract: New chemotherapeutics active against multidrug-resistant Mycobacterium tuberculosis (M. tb) are urgently needed. We report on the identification of an adamantyl urea compound displaying potent bactericidal activity against M. tb 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 where they are transferred onto cell wall arabinogalactan or used in the formation of virulence-associate… Show more

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...
3
1

Citation Types

23
573
4

Year Published

2014
2014
2019
2019

Publication Types

Select...
7
1

Relationship

0
8

Authors

Journals

citations
Cited by 381 publications
(600 citation statements)
references
References 48 publications
23
573
4
Order By: Relevance
“…Interestingly, promising new compounds, which recently emerged from different screening programs, also target various steps in cell envelope metabolism (reviewed in reference 7). These are exemplified by (i) the inhibitors of MmpL3 (8)(9)(10)(11)(12), the trehalose monomycolate transporter required for the proper localization of mycolic acids, and (ii) the inhibitors of the decaprenyl-phosphoribose 2=-oxidoreductase DprE1 (11,(13)(14)(15), involved in the biosynthesis of mycobacterial AG and LAM. Specifically, DprE1 inhibitors block the biosynthetic pathway of the arabinan precursor and, therefore, the buildup of a covalently linked complex of mycolic acids, AG, and peptidoglycan, which form the so-called cell wall core (16).…”
mentioning
confidence: 99%
“…Interestingly, promising new compounds, which recently emerged from different screening programs, also target various steps in cell envelope metabolism (reviewed in reference 7). These are exemplified by (i) the inhibitors of MmpL3 (8)(9)(10)(11)(12), the trehalose monomycolate transporter required for the proper localization of mycolic acids, and (ii) the inhibitors of the decaprenyl-phosphoribose 2=-oxidoreductase DprE1 (11,(13)(14)(15), involved in the biosynthesis of mycobacterial AG and LAM. Specifically, DprE1 inhibitors block the biosynthetic pathway of the arabinan precursor and, therefore, the buildup of a covalently linked complex of mycolic acids, AG, and peptidoglycan, which form the so-called cell wall core (16).…”
mentioning
confidence: 99%
“…Because DAT, TAT, TetraAT, and PAT are all found at the cell surface, this model implies that MmpL10 transports all of these lipids across the cytoplasmic membrane. This substrate promiscuity would distinguish MmpL10 from previously characterized MmpLs such as MmpL7 and MmpL3, which exclusively transport phthiocerol mycocerosate (PDIM) and trehalose monomycolate (TMM), respectively (41)(42)(43). On the other hand, in sulfolipid 1 biosynthesis, when Chp1 is absent, the diacylated sulfotrehalose intermediate SL 1278 (also known as Ac 2 SGL) is detected at the cell surface, suggesting that MmpL8 is capable of transporting this intermediate in addition to SL-1 and shares the ability to transport multiple substrates with MmpL10, which is a closely related homologue (58% sequence identity).…”
Section: Discussionmentioning
confidence: 99%
“…9 Instead, there is strong evidence that these MmpL transporters and their MmpS accessory proteins are responsible for shuttling fatty acid and lipid components of the cell wall, such as trehalose monomycolate, sulfolipids, phthiocerol dimycocerosate, diacyltrehalose, monomeromycolyl diacylglycerol, and mycolate wax ester. 3,9,11,12,[19][20][21][22][23] The regulation of MmpL protein expression and the role of MmpLs in cell wall remodeling in different environmental conditions has not been explored. Thus we capitalized on data made available by the TB Systems Biology Consortium to begin an in-depth analysis of how mmpL and mmpS genes are regulated.…”
Section: Introductionmentioning
confidence: 99%
“…MmpL3 is essential; MmpL4, MmpL5, MmpL7, MmpL8, MmpL10, and MmpL11 are required for full Mtb virulence. [9][10][11][12] MmpL3 transports the trehalose dimycolate (TDM) precursor trehalose monomycolate to the mycobacterial surface. 12 MmpL3 is therefore essential since TDM biosynthesis and incorporation into the mycobacterial cell wall is required for mycobacterial replication and viability.…”
Section: Introductionmentioning
confidence: 99%
See 1 more Smart Citation