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 (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 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.
Highlights
Tuberculosis (TB) accounts for 1.5 million deaths worldwide every year, with a high percentage of individuals primarily from developing nations (WHO, 2012)
MtArgJ belongs to the N-terminal nucleophile (Ntn) fold class of enzymes, synthesized as a 404-amino acid long protein, which undergoes an auto-proteolysis event between the Ala199 and Thr200
Targeting MtArgJ for anti-TB drug development is advantageous for two main reasons: (i) It is an essential gene for the survival and virulence of the pathogen (Sassetti & Rubin, 2003; Sassetti et al, 2003), and (ii) it lacks a homologous protein in human genome
Summary
Tuberculosis (TB) accounts for 1.5 million deaths worldwide every year, with a high percentage of individuals primarily from developing nations (WHO, 2012). Emergence of drug-resistant strains has further increased the Mycobacterium tuberculosis (Mtb)-associated lethality. Itself there have been enormous attempts toward the development of novel therapeutic approaches to combat multi-drug-resistant (MDR) and extensively drug-resistant (XDR) Mtb strains (Makarov et al, 2009, 2014; Koul et al, 2011). Novel therapy regimens endorse strategies wherein the pre-approved drugs for other ailments could be re-purposed for targeting lethal Mtb strains (Zumla et al, 2013). The major challenges in finding a suitable target for anti-Mtb drug discovery is its ever-evolving stride and the conserved nature of the essential proteins (Zuniga et al, 2015). The past decade has seen major developments in the TB drug discovery pipeline, still there is a constant need for improved therapeutic interventions (Zumla et al, 2013)
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