Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis
© 2018 American Chemical Society. Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal Article |
| Published: |
American Chemical Society
2018
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| Online Access: | http://purl.org/au-research/grants/arc/DE160100482 http://hdl.handle.net/20.500.11937/66509 |
| _version_ | 1848761339041808384 |
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| author | Zhang, W. Lun, S. Wang, S. Jiang, X. Yang, F. Tang, J. Manson, A. Earl, A. Gunosewoyo, Hendra Bishai, W. Yu, L. |
| author_facet | Zhang, W. Lun, S. Wang, S. Jiang, X. Yang, F. Tang, J. Manson, A. Earl, A. Gunosewoyo, Hendra Bishai, W. Yu, L. |
| author_sort | Zhang, W. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | © 2018 American Chemical Society. Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure-activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form coumestans that are shown to be active in SIT. Whole genome deep sequencing of the coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of this target for the development of new antitubercular agents. |
| first_indexed | 2025-11-14T10:30:06Z |
| format | Journal Article |
| id | curtin-20.500.11937-66509 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T10:30:06Z |
| publishDate | 2018 |
| publisher | American Chemical Society |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-665092018-07-11T06:17:17Z Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis Zhang, W. Lun, S. Wang, S. Jiang, X. Yang, F. Tang, J. Manson, A. Earl, A. Gunosewoyo, Hendra Bishai, W. Yu, L. © 2018 American Chemical Society. Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure-activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form coumestans that are shown to be active in SIT. Whole genome deep sequencing of the coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of this target for the development of new antitubercular agents. 2018 Journal Article http://hdl.handle.net/20.500.11937/66509 10.1021/acs.jmedchem.7b01319 http://purl.org/au-research/grants/arc/DE160100482 American Chemical Society restricted |
| spellingShingle | Zhang, W. Lun, S. Wang, S. Jiang, X. Yang, F. Tang, J. Manson, A. Earl, A. Gunosewoyo, Hendra Bishai, W. Yu, L. Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis |
| title | Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis |
| title_full | Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis |
| title_fullStr | Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis |
| title_full_unstemmed | Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis |
| title_short | Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis |
| title_sort | identification of novel coumestan derivatives as polyketide synthase 13 inhibitors against mycobacterium tuberculosis |
| url | http://purl.org/au-research/grants/arc/DE160100482 http://hdl.handle.net/20.500.11937/66509 |