High throughput screen identifies small molecule inhibitors specific for Mycobacterium tuberculosis phosphoserine phosphatase.

Arora, Garima and Tiwari, Prabhakar and Mandal, Rahul Shubhra and Gupta, Arpit and Sharma, Deepak and Saha, Sudipto and Singh, Ramandeep (2014) High throughput screen identifies small molecule inhibitors specific for Mycobacterium tuberculosis phosphoserine phosphatase. The Journal of biological chemistry, 289 (36). pp. 25149-65. ISSN 1083-351X

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Official URL: http://www.jbc.org/content/289/36/25149.long

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.

Item Type: Article
Additional Information: Copyright of this article belongs to ASBMB.
Uncontrolled Keywords: Bacterial Protein Phosphatase; Enzyme Kinetics; High Throughput Screening (HTS); Molecular Docking; Mycobacterium tuberculosis
Subjects: Q Science > QR Microbiology
Depositing User: Dr. K.P.S.Sengar
Date Deposited: 20 Jul 2015 05:13
Last Modified: 20 Jul 2015 05:13
URI: http://crdd.osdd.net/open/id/eprint/1681

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