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Title: Novel acetamide indirectly targets mycobacterial transporter MmpL3 by proton motive force disruption
Authors: Shetty, Annanya
Xu, Zhujun
Lakshmanan, Umayal
Hill, Jeffrey
Choong, Meng Ling
Chng, Shu-Sin
Yamada, Yoshiyuki
Poulsen, Anders
Dick, Thomas
Gengenbacher, Martin
Keywords: DRNTU::Engineering::Environmental engineering
Mycobacterium Tuberculosis
Cell Envelope Stress
Issue Date: 2018
Source: Shetty, A., Xu, Z., Lakshmanan, U., Hill, J., Choong, M. L., Chng, S.-S., . . . Gengenbacher, M. (2018). Novel acetamide indirectly targets mycobacterial transporter MmpL3 by proton motive force disruption. Frontiers in Microbiology, 9, 2960-. doi:10.3389/fmicb.2018.02960
Series/Report no.: Frontiers in Microbiology
Abstract: To identify novel inhibitors of Mycobacterium tuberculosis cell envelope biosynthesis, we employed a two-step approach. First, we screened the diverse synthetic small molecule 71,544-compound Enamine library for growth inhibitors using the non-pathogenic surrogate Mycobacterium bovis BCG as screening strain and turbidity as readout. Second, 16 confirmed hits were tested for their ability to induce the cell envelope stress responsive promoter piniBAC controlling expression of red fluorescent protein in an M. bovis BCG reporter strain. Using a fluorescence readout, the acetamide E11 was identified. Resistant mutant selection and whole genome sequencing revealed the mycolic acid transporter Mmpl3 as a candidate target of E11. Biochemical analysis using mycobacterial spheroplasts and various membrane assays suggest that E11 indirectly inhibits MmpL3-facilitated translocation of trehalose monomycolates by proton motive force disruption. E11 showed potent bactericidal activity against growing and non-growing M. tuberculosis, low cytotoxic, and hemolytic activity and a dynamic structure activity relationship. In addition to activity against M. tuberculosis, E11 was active against the non-tuberculous mycobacterium M. abscessus, an emerging opportunistic pathogen. In conclusion, we identified a novel bactericidal anti-mycobacterial lead compound targeting MmpL3 providing an attractive starting point for optimization.
DOI: 10.3389/fmicb.2018.02960
Rights: © 2018 Shetty, Xu, Lakshmanan, Hill, Choong, Chng, Yamada, Poulsen, Dick and Gengenbacher. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Fulltext Permission: open
Fulltext Availability: With Fulltext
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