Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis.
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 disco...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3781026?pdf=render |
| _version_ | 1830358183443431424 |
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| author | Thomas R Ioerger Theresa O'Malley Reiling Liao Kristine M Guinn Mark J Hickey Nilofar Mohaideen Kenan C Murphy Helena I M Boshoff Valerie Mizrahi Eric J Rubin Christopher M Sassetti Clifton E Barry David R Sherman Tanya Parish James C Sacchettini |
| author_facet | Thomas R Ioerger Theresa O'Malley Reiling Liao Kristine M Guinn Mark J Hickey Nilofar Mohaideen Kenan C Murphy Helena I M Boshoff Valerie Mizrahi Eric J Rubin Christopher M Sassetti Clifton E Barry David R Sherman Tanya Parish James C Sacchettini |
| author_sort | Thomas R Ioerger |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T02:36:14Z |
| format | Article |
| id | doaj.art-c0d9c992417546e4bc77aaa58b2066b1 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T02:36:14Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c0d9c992417546e4bc77aaa58b2066b12022-12-21T19:56:26ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0189e7524510.1371/journal.pone.0075245Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis.Thomas R IoergerTheresa O'MalleyReiling LiaoKristine M GuinnMark J HickeyNilofar MohaideenKenan C MurphyHelena I M BoshoffValerie MizrahiEric J RubinChristopher M SassettiClifton E BarryDavid R ShermanTanya ParishJames C SacchettiniIdentification 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.http://europepmc.org/articles/PMC3781026?pdf=render |
| spellingShingle | Thomas R Ioerger Theresa O'Malley Reiling Liao Kristine M Guinn Mark J Hickey Nilofar Mohaideen Kenan C Murphy Helena I M Boshoff Valerie Mizrahi Eric J Rubin Christopher M Sassetti Clifton E Barry David R Sherman Tanya Parish James C Sacchettini Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis. PLoS ONE |
| title | Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis. |
| title_full | Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis. |
| title_fullStr | Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis. |
| title_full_unstemmed | Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis. |
| title_short | Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis. |
| title_sort | identification of new drug targets and resistance mechanisms in mycobacterium tuberculosis |
| url | http://europepmc.org/articles/PMC3781026?pdf=render |
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