Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis

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dc.contributor.authorIoerger, Thomas Ren_ZA
dc.contributor.authorO'Malley, Theresaen_ZA
dc.contributor.authorLiao, Reilingen_ZA
dc.contributor.authorGuinn, Kristine Men_ZA
dc.contributor.authorHickey, Mark Jen_ZA
dc.contributor.authorMohaideen, Nilofaren_ZA
dc.contributor.authorMurphy, Kenan Cen_ZA
dc.contributor.authorBoshoff, Helena I Men_ZA
dc.contributor.authorMizrahi, Valerieen_ZA
dc.contributor.authorRubin, Eric Jen_ZA
dc.date.accessioned2016-01-02T05:05:49Z
dc.date.available2016-01-02T05:05:49Z
dc.date.issued2013en_ZA
dc.description.abstractIdentification of new drug targets is vital for the advancement of drug discovery against Mycobacterium tuberculosis , especially given the increase of resistance worldwide to first- and second-line drugs. Because traditional target-based screening has largely proven unsuccessful for antibiotic discovery, we have developed a scalable platform for target identification in M. tuberculosis that is based on whole-cell screening, coupled with whole-genome sequencing of resistant mutants and recombineering to confirm. The method yields targets paired with whole-cell active compounds, which can serve as novel scaffolds for drug development, molecular tools for validation, and/or as ligands for co-crystallization. It may also reveal other information about mechanisms of action, such as activation or efflux. Using this method, we identified resistance-linked genes for eight compounds with anti-tubercular activity. Four of the genes have previously been shown to be essential: AspS, aspartyl-tRNA synthetase, Pks13, a polyketide synthase involved in mycolic acid biosynthesis, MmpL3, a membrane transporter, and EccB3, a component of the ESX-3 type VII secretion system. AspS and Pks13 represent novel targets in protein translation and cell-wall biosynthesis. Both MmpL3 and EccB3 are involved in membrane transport. Pks13, AspS, and EccB3 represent novel candidates not targeted by existing TB drugs, and the availability of whole-cell active inhibitors greatly increases their potential for drug discovery.en_ZA
dc.identifier.apacitationIoerger, T. R., O'Malley, T., Liao, R., Guinn, K. M., Hickey, M. J., Mohaideen, N., ... Rubin, E. J. (2013). Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis. <i>PLoS One</i>, http://hdl.handle.net/11427/16165en_ZA
dc.identifier.chicagocitationIoerger, Thomas R, Theresa O'Malley, Reiling Liao, Kristine M Guinn, Mark J Hickey, Nilofar Mohaideen, Kenan C Murphy, Helena I M Boshoff, Valerie Mizrahi, and Eric J Rubin "Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis." <i>PLoS One</i> (2013) http://hdl.handle.net/11427/16165en_ZA
dc.identifier.citationIoerger, T. R., O’Malley, T., Liao, R., Guinn, K. M., Hickey, M. J., Mohaideen, N., ... & Sassetti, C. M. (2013). Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis. PLoS One, 8(9), e75245. doi:10.1371/journal.pone.0075245en_ZA
dc.identifier.ris TY - Journal Article AU - Ioerger, Thomas R AU - O'Malley, Theresa AU - Liao, Reiling AU - Guinn, Kristine M AU - Hickey, Mark J AU - Mohaideen, Nilofar AU - Murphy, Kenan C AU - Boshoff, Helena I M AU - Mizrahi, Valerie AU - Rubin, Eric J AB - Identification of new drug targets is vital for the advancement of drug discovery against Mycobacterium tuberculosis , especially given the increase of resistance worldwide to first- and second-line drugs. Because traditional target-based screening has largely proven unsuccessful for antibiotic discovery, we have developed a scalable platform for target identification in M. tuberculosis that is based on whole-cell screening, coupled with whole-genome sequencing of resistant mutants and recombineering to confirm. The method yields targets paired with whole-cell active compounds, which can serve as novel scaffolds for drug development, molecular tools for validation, and/or as ligands for co-crystallization. It may also reveal other information about mechanisms of action, such as activation or efflux. Using this method, we identified resistance-linked genes for eight compounds with anti-tubercular activity. Four of the genes have previously been shown to be essential: AspS, aspartyl-tRNA synthetase, Pks13, a polyketide synthase involved in mycolic acid biosynthesis, MmpL3, a membrane transporter, and EccB3, a component of the ESX-3 type VII secretion system. AspS and Pks13 represent novel targets in protein translation and cell-wall biosynthesis. Both MmpL3 and EccB3 are involved in membrane transport. Pks13, AspS, and EccB3 represent novel candidates not targeted by existing TB drugs, and the availability of whole-cell active inhibitors greatly increases their potential for drug discovery. DA - 2013 DB - OpenUCT DO - 10.1371/journal.pone.0075245 DP - University of Cape Town J1 - PLoS One LK - https://open.uct.ac.za PB - University of Cape Town PY - 2013 T1 - Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis TI - Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis UR - http://hdl.handle.net/11427/16165 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/16165
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pone.0075245
dc.identifier.vancouvercitationIoerger TR, O'Malley T, Liao R, Guinn KM, Hickey MJ, Mohaideen N, et al. Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis. PLoS One. 2013; http://hdl.handle.net/11427/16165.en_ZA
dc.language.isoengen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.publisher.departmentInstitute of Infectious Disease and Molecular Medicineen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_ZA
dc.rights.holder© 2013 Ioerger et alen_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0en_ZA
dc.sourcePLoS Oneen_ZA
dc.source.urihttp://journals.plos.org/plosoneen_ZA
dc.subject.otherMycobacterium tuberculosisen_ZA
dc.subject.otherDrug discoveryen_ZA
dc.subject.otherTuberculosis drug discoveryen_ZA
dc.subject.otherLiquidsen_ZA
dc.subject.otherGene targetingen_ZA
dc.subject.otherInsertion mutationen_ZA
dc.subject.otherTransformation associated recombinationen_ZA
dc.subject.otherTransposable elementsen_ZA
dc.titleIdentification of new drug targets and resistance mechanisms in Mycobacterium tuberculosisen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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