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dc.contributor.authorShetty, Annanyaen
dc.contributor.authorXu, Zhujunen
dc.contributor.authorLakshmanan, Umayalen
dc.contributor.authorHill, Jeffreyen
dc.contributor.authorChoong, Meng Lingen
dc.contributor.authorChng, Shu-Sinen
dc.contributor.authorYamada, Yoshiyukien
dc.contributor.authorPoulsen, Andersen
dc.contributor.authorDick, Thomasen
dc.contributor.authorGengenbacher, Martinen
dc.identifier.citationShetty, 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.2018.02960en
dc.description.abstractTo 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.en
dc.description.sponsorshipMOE (Min. of Education, S’pore)en
dc.description.sponsorshipNMRC (Natl Medical Research Council, S’pore)en
dc.description.sponsorshipMOH (Min. of Health, S’pore)en
dc.format.extent12 p.en
dc.relation.ispartofseriesFrontiers in Microbiologyen
dc.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.en
dc.subjectDRNTU::Engineering::Environmental engineeringen
dc.subjectMycobacterium Tuberculosisen
dc.subjectCell Envelope Stressen
dc.titleNovel acetamide indirectly targets mycobacterial transporter MmpL3 by proton motive force disruptionen
dc.typeJournal Articleen
dc.contributor.organizationSingapore Centre for Environmental Life Sciences Engineeringen
dc.description.versionPublished versionen
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