Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen
High-throughput phenotypic screens have re-emerged as screening tools in antibiotic discovery. The advent of such technologies has rapidly accelerated the identification of 'hit' compounds. A pre-requisite to medicinal chemistry optimisation programmes required to improve the drug-like pro...
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Nature Research
2022
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| Online Access: | https://www.nature.com/articles/srep38986 http://hdl.handle.net/11408/4905 |
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| author | Cox, Jonathan A G Mugumbate, Grace Peral, Laura Vela-Glez Del Jankute, Monika Abrahams, Katherine A Jervis, Peter Jackenkroll, Stefan Perez, Arancha Alemparte, Carlos Esquivias, Jorge Lelièvre, Joël Ramon, Fernando Barros, David Ballell, Lluis Besra, Gurdyal S |
| author_facet | Cox, Jonathan A G Mugumbate, Grace Peral, Laura Vela-Glez Del Jankute, Monika Abrahams, Katherine A Jervis, Peter Jackenkroll, Stefan Perez, Arancha Alemparte, Carlos Esquivias, Jorge Lelièvre, Joël Ramon, Fernando Barros, David Ballell, Lluis Besra, Gurdyal S |
| author_sort | Cox, Jonathan A G |
| collection | DSpace |
| description | High-throughput phenotypic screens have re-emerged as screening tools in antibiotic discovery. The advent of such technologies has rapidly accelerated the identification of 'hit' compounds. A pre-requisite to medicinal chemistry optimisation programmes required to improve the drug-like properties of a 'hit' molecule is identification of its mode of action. Herein, we have combined phenotypic screening with a biased target-specific screen. The inosine monophosphate dehydrogenase (IMPDH) protein GuaB2 has been identified as a drugable target in Mycobacterium tuberculosis, however previously identified compounds lack the desired characteristics necessary for further development into lead-like molecules. This study has identified 7 new chemical series from a high-throughput resistance-based phenotypic screen using Mycobacterium bovis BCG over-expressing GuaB2. Hit compounds were identified in a single shot high-throughput screen, validated by dose response and subjected to further biochemical analysis. The compounds were also assessed using molecular docking experiments, providing a platform for their further optimisation using medicinal chemistry. This work demonstrates the versatility and potential of GuaB2 as an anti-tubercular drug target. |
| format | Article |
| id | ir-11408-4905 |
| institution | My University |
| language | English |
| publishDate | 2022 |
| publisher | Nature Research |
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| spelling | ir-11408-49052022-06-28T09:51:03Z Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen Cox, Jonathan A G Mugumbate, Grace Peral, Laura Vela-Glez Del Jankute, Monika Abrahams, Katherine A Jervis, Peter Jackenkroll, Stefan Perez, Arancha Alemparte, Carlos Esquivias, Jorge Lelièvre, Joël Ramon, Fernando Barros, David Ballell, Lluis Besra, Gurdyal S Antibiotics High-throughput screening Phenotypic screening Target validation High-throughput phenotypic screens have re-emerged as screening tools in antibiotic discovery. The advent of such technologies has rapidly accelerated the identification of 'hit' compounds. A pre-requisite to medicinal chemistry optimisation programmes required to improve the drug-like properties of a 'hit' molecule is identification of its mode of action. Herein, we have combined phenotypic screening with a biased target-specific screen. The inosine monophosphate dehydrogenase (IMPDH) protein GuaB2 has been identified as a drugable target in Mycobacterium tuberculosis, however previously identified compounds lack the desired characteristics necessary for further development into lead-like molecules. This study has identified 7 new chemical series from a high-throughput resistance-based phenotypic screen using Mycobacterium bovis BCG over-expressing GuaB2. Hit compounds were identified in a single shot high-throughput screen, validated by dose response and subjected to further biochemical analysis. The compounds were also assessed using molecular docking experiments, providing a platform for their further optimisation using medicinal chemistry. This work demonstrates the versatility and potential of GuaB2 as an anti-tubercular drug target. 2022-06-28T09:51:03Z 2022-06-28T09:51:03Z 2016 Article 2045-2322 DOI: 10.1038/srep38986 https://www.nature.com/articles/srep38986 http://hdl.handle.net/11408/4905 en Scientific reports;Vol. 6,No. 38986 open Nature Research |
| spellingShingle | Antibiotics High-throughput screening Phenotypic screening Target validation Cox, Jonathan A G Mugumbate, Grace Peral, Laura Vela-Glez Del Jankute, Monika Abrahams, Katherine A Jervis, Peter Jackenkroll, Stefan Perez, Arancha Alemparte, Carlos Esquivias, Jorge Lelièvre, Joël Ramon, Fernando Barros, David Ballell, Lluis Besra, Gurdyal S Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen |
| title | Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen |
| title_full | Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen |
| title_fullStr | Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen |
| title_full_unstemmed | Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen |
| title_short | Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen |
| title_sort | novel inhibitors of mycobacterium tuberculosis guab2 identified by a target based high-throughput phenotypic screen |
| topic | Antibiotics High-throughput screening Phenotypic screening Target validation |
| url | https://www.nature.com/articles/srep38986 http://hdl.handle.net/11408/4905 |
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