Screening and Identification of a Novel Anti-tuberculosis Compound That Targets Deoxyuridine 5′-Triphosphate Nucleotidohydrolase
Tuberculosis (TB) is still a threat to humans worldwide. The rise of drug-resistant TB strains has escalated the need for developing effective anti-TB agents. Deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) is essential for thymidylate biosynthesis to maintain the DNA integrity. In Mycoba...
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Frontiers Media S.A.
2021-10-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2021.757914/full |
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| author | Yu Zhang Hongjuan Zhang Ying Chen Luyao Qiao Yanxing Han Yuan Lin Shuyi Si Jian-Dong Jiang Jian-Dong Jiang |
| author_facet | Yu Zhang Hongjuan Zhang Ying Chen Luyao Qiao Yanxing Han Yuan Lin Shuyi Si Jian-Dong Jiang Jian-Dong Jiang |
| author_sort | Yu Zhang |
| collection | DOAJ |
| description | Tuberculosis (TB) is still a threat to humans worldwide. The rise of drug-resistant TB strains has escalated the need for developing effective anti-TB agents. Deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) is essential for thymidylate biosynthesis to maintain the DNA integrity. In Mycobacterium tuberculosis, dUTPase provides the sole source for thymidylate biosynthesis, which also has the specific five-residue loop and the binding pockets absent in human dUTPase. Therefore, dUTPase has been regarded as a promising anti-TB drug target. Herein, we used a luminescence-based dUTPase assay to search for the inhibitors target M. tuberculosis dUTPase (Mt-dUTPase) and identified compound F0414 as a potent Mt-dUTPase inhibitor with an IC50 of 0.80 ± 0.09 μM. F0414 exhibited anti-TB activity with low cytotoxicity. Molecular docking model and site-directed mutation experiments revealed that P79 was the key residue in the interaction of Mt-dUTPase and F0414. Moreover, F0414 was shown to have stronger binding with Mt-dUTPase than with Mt-P79A-dUTPase by surface plasmon resonance (SPR) detection. Interestingly, F0414 exhibited insensitivity and weak directly binding on human dUTPase compared with that on Mt-dUTPase. All the results highlight that F0414 is the first compound reported to have anti-TB activity by inhibiting Mt-dUTPase, which indicates the potential application in anti-TB therapy. |
| first_indexed | 2024-12-22T08:33:49Z |
| format | Article |
| id | doaj.art-047eaedec5814ec0a5ccb93c0f47e3fc |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-22T08:33:49Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-047eaedec5814ec0a5ccb93c0f47e3fc2022-12-21T18:32:25ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2021-10-011210.3389/fmicb.2021.757914757914Screening and Identification of a Novel Anti-tuberculosis Compound That Targets Deoxyuridine 5′-Triphosphate NucleotidohydrolaseYu Zhang0Hongjuan Zhang1Ying Chen2Luyao Qiao3Yanxing Han4Yuan Lin5Shuyi Si6Jian-Dong Jiang7Jian-Dong Jiang8State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaState Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaState Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaState Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaState Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaState Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaState Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaTuberculosis (TB) is still a threat to humans worldwide. The rise of drug-resistant TB strains has escalated the need for developing effective anti-TB agents. Deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase) is essential for thymidylate biosynthesis to maintain the DNA integrity. In Mycobacterium tuberculosis, dUTPase provides the sole source for thymidylate biosynthesis, which also has the specific five-residue loop and the binding pockets absent in human dUTPase. Therefore, dUTPase has been regarded as a promising anti-TB drug target. Herein, we used a luminescence-based dUTPase assay to search for the inhibitors target M. tuberculosis dUTPase (Mt-dUTPase) and identified compound F0414 as a potent Mt-dUTPase inhibitor with an IC50 of 0.80 ± 0.09 μM. F0414 exhibited anti-TB activity with low cytotoxicity. Molecular docking model and site-directed mutation experiments revealed that P79 was the key residue in the interaction of Mt-dUTPase and F0414. Moreover, F0414 was shown to have stronger binding with Mt-dUTPase than with Mt-P79A-dUTPase by surface plasmon resonance (SPR) detection. Interestingly, F0414 exhibited insensitivity and weak directly binding on human dUTPase compared with that on Mt-dUTPase. All the results highlight that F0414 is the first compound reported to have anti-TB activity by inhibiting Mt-dUTPase, which indicates the potential application in anti-TB therapy.https://www.frontiersin.org/articles/10.3389/fmicb.2021.757914/fullanti-tuberculosisdUTPasehigh-throughput screeninginhibitormolecular docking |
| spellingShingle | Yu Zhang Hongjuan Zhang Ying Chen Luyao Qiao Yanxing Han Yuan Lin Shuyi Si Jian-Dong Jiang Jian-Dong Jiang Screening and Identification of a Novel Anti-tuberculosis Compound That Targets Deoxyuridine 5′-Triphosphate Nucleotidohydrolase Frontiers in Microbiology anti-tuberculosis dUTPase high-throughput screening inhibitor molecular docking |
| title | Screening and Identification of a Novel Anti-tuberculosis Compound That Targets Deoxyuridine 5′-Triphosphate Nucleotidohydrolase |
| title_full | Screening and Identification of a Novel Anti-tuberculosis Compound That Targets Deoxyuridine 5′-Triphosphate Nucleotidohydrolase |
| title_fullStr | Screening and Identification of a Novel Anti-tuberculosis Compound That Targets Deoxyuridine 5′-Triphosphate Nucleotidohydrolase |
| title_full_unstemmed | Screening and Identification of a Novel Anti-tuberculosis Compound That Targets Deoxyuridine 5′-Triphosphate Nucleotidohydrolase |
| title_short | Screening and Identification of a Novel Anti-tuberculosis Compound That Targets Deoxyuridine 5′-Triphosphate Nucleotidohydrolase |
| title_sort | screening and identification of a novel anti tuberculosis compound that targets deoxyuridine 5 triphosphate nucleotidohydrolase |
| topic | anti-tuberculosis dUTPase high-throughput screening inhibitor molecular docking |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2021.757914/full |
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