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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Gupta, Arpit Mandal, Rahul Shubhra Tiwari, Prabhakar Sharma, Deepak Saha, Sudipto Singh, Ramandeep Arora, Garima |
| Description | Author Affiliation: Arora G ( From the Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, Gurgaon 122016, Haryana, India, the Symbiosis School of Biomedical Sciences, Symbiosis International University, Lavale, Maharashtra 412115, India.); Tiwari P ( From the Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, Gurgaon 122016, Haryana, India.); Mandal RS ( the Biomedical Informatics Center, National Institute of Cholera and Enteric Diseases, Kolkata, West Bengal 700010, India.); Gupta A ( the CSIR-Institute of Microbial Technology, Chandigarh, 160036, India, and.); Sharma D ( the CSIR-Institute of Microbial Technology, Chandigarh, 160036, India, and.); Saha S ( the Bioinformatics Centre, Bose Institute, Kolkata, West Bengal 700054, India.); Singh R ( From the Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, Gurgaon 122016, Haryana, India, ramandeep@thsti.res.in.) |
| Abstract | The emergence of drug-resistant strains of Mycobacterium tuberculosis makes identification and validation of newer drug targets a global priority. Phosphoserine phosphatase (PSP), a key essential metabolic enzyme involved in conversion of O-phospho-l-serine to l-serine, was characterized in this study. The M. tuberculosis genome harbors all enzymes involved in l-serine biosynthesis including two PSP homologs: Rv0505c (SerB1) and Rv3042c (SerB2). In the present study, we have biochemically characterized SerB2 enzyme and developed malachite green-based high throughput assay system to identify SerB2 inhibitors. We have identified 10 compounds that were structurally different from known PSP inhibitors, and few of these scaffolds were highly specific in their ability to inhibit SerB2 enzyme, were noncytotoxic against mammalian cell lines, and inhibited M. tuberculosis growth in vitro. Surface plasmon resonance experiments demonstrated the relative binding for these inhibitors. The two best hits identified in our screen, clorobiocin and rosaniline, were bactericidal in activity and killed intracellular bacteria in a dose-dependent manner. We have also identified amino acid residues critical for these SerB2-small molecule interactions. This is the first study where we validate that M. tuberculosis SerB2 is a druggable and suitable target to pursue for further high throughput assay system screening. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 36 |
| Volume Number | 289 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2014-09-05 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Bacterial Proteins Metabolism Enzyme Inhibitors Pharmacology High-Throughput Screening Assays Mycobacterium Tuberculosis Enzymology Phosphoric Monoester Hydrolases Antagonists & Inhibitors Amino Acid Sequence Antitubercular Agents Chemistry Genetics Cell Line, Tumor Kinetics Microbial Sensitivity Tests Models, Molecular Molecular Sequence Data Molecular Structure Drug Effects Novobiocin Analogs & Derivatives Classification Phylogeny Protein Binding Protein Structure, Tertiary Rosaniline Dyes Sequence Homology, Amino Acid Small Molecule Libraries Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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