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An allosteric inhibitor of Mycobacterium tuberculosis ArgJ: Implications to a novel combinatorial therapy

Mishra, Archita and Mamidi, Ashalatha S and Rajmani, Raju S and Ray, Ananya and Roy, Rajanya and Surolia, Avadhesha (2018) An allosteric inhibitor of Mycobacterium tuberculosis ArgJ: Implications to a novel combinatorial therapy. In: EMBO MOLECULAR MEDICINE, 10 (4).

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Official URL: http://dx.doi.org/10.15252/emmm.201708038


The existing treatment regime against tuberculosis is not adequate, and novel therapeutic interventions are required to target Mycobacterium tuberculosis (Mtb) pathogenesis. We report Pranlukast (PRK) as a novel allosteric inhibitor of Mtb's arginine biosynthetic enzyme, Ornithine acetyltransferase (MtArgJ). PRK treatment remarkably abates the survival of free as well as macrophage-internalized Mtb, and shows enhanced efficacy in combination with standard-of-care drugs. Notably, PRK also reduces the 5-lipoxygenase (5-LO) signaling in the infected macrophages, thereby surmounting an enhanced response against intracellular pathogen. Further, treatment with PRK alone or with rifampicin leads to significant decrease in Mtb burden and tubercular granulomas in Mtb-infected mice lungs. Taken together, this study demonstrates a novel allosteric inhibitor of MtArgJ, which acts as a dual-edged sword, by targeting the intracellular bacteria as well as the bacterial pro-survival signaling in the host. PRK is highly effective against invitro and invivo survival of Mtb and being an FDA-approved drug, it shows a potential for development of advanced combinatorial therapy against tuberculosis.

Item Type: Journal Article
Additional Information: Copy right for this article belong to WILEY, 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Division of Biological Sciences > Microbiology & Cell Biology
Depositing User: Id for Latest eprints
Date Deposited: 04 May 2018 18:47
Last Modified: 04 May 2018 18:47
URI: http://eprints.iisc.ac.in/id/eprint/59760

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