An allosteric inhibitor of Mycobacterium tuberculosis ArgJ: Implications to a novel combinatorial therapy. Issue 4 (26th February 2018)

• Record Type: Journal Article
• Authors: Mishra, Archita; Mamidi, Ashalatha S; Rajmani, Raju S; Ray, Ananya; Roy, Rajanya; Surolia, Avadhesha
• Is Part Of: EMBO molecular medicine. Volume 10:Issue 4(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-02-26
• Subjects: combinatorial therapy -- drug repurposing -- infectious disease -- Mycobacterium tuberculosis -- Ornithine acetyltransferase; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201708038
• Languages: English
• ISSNs: 1757-4676

Abstract

Abstract: 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 ( Mt ArgJ). 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 Mt ArgJ, 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 in vitro and in vivo survival of Mtb and being an FDA‐approved drug, it shows a potential for development of advanced combinatorial therapy against tuberculosis. Synopsis: Mycobacterium tuberculosis ( Mtb ) is an infectious pathogen claiming millions of lives worldwide. This study identifies a novel inhibitor against the Mt ArgJ enzyme of the arginine biosynthesis pathway, essential for pathogenicity and survival, and establishes its efficacy in pre‐clinical models. In silico and in vitro FDA approved drugs were screened to target an allosteric site on Mt ArgJ and Pranlukast (PRK) was identified as a potent inhibitor. PRK treatment reduced Mtb survival both in vitro and in infected macrophages. PRK efficiently reduced the lung associated Mtb burden and tubercular granulomas in mouse models of infection. PRK inhibited Mtb survival in vivo by dual mechanisms, through targeting arginine biosynthesis of the pathogen and inhibiting the Mtb pro‐survival signaling (5‐LO) in the host. PRK potentiated the effect of Rifampicin (Rif) in vivo, thereby introducing a novel combination (Rif with PRK) towards therapeutic regime for tuberculosis. Abstract : Mycobacterium tuberculosis ( Mtb ) is an infectious pathogen claiming millions of lives worldwide. This study identifies a novel inhibitor against the Mt ArgJ enzyme of the arginine biosynthesis pathway, essential for pathogenicity and survival, and establishes its efficacy in pre‐clinical models.