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

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.

Allosteric regulation of menaquinone (vitamin K2) biosynthesis in the human pathogen Mycobacterium tuberculosis

“…Importantly, however, the presence of a site with a powerful ability to regulate enzyme activity is of immediate value as a species-specific antimicrobial target. The field of allosteric inhibition is a growing one (46). Allosteric inhibitors have been recently exploited to inhibit M. tuberculosis growth through inhibiting Mtb ArgJ (47) and Mtb TrpB (48).…”

“…Allosteric inhibitors have been recently exploited to inhibit M. tuberculosis growth through inhibiting Mtb ArgJ (47) and Mtb TrpB (48). Whereas allosteric inhibitors in general do not completely inhibit their targets (46), they exhibit greater specificity compared with the active-site inhibitors (48). Moreover, allosteric sites show greater propensity to bind more hydrophobic molecules, often correlated with more desirable cell permeability properties (48).…”

Integrated Computational Approaches and Tools for Allosteric Drug Discovery

“…The protein pyruvate kinase was observed to exhibit some allosteric mechanism and deemed an attractive target of Mtb therapy [128]. Similarly, an allosteric inhibitor was identified for the Mtb enzyme ornithine acetyltransferase [129] and yet another for the enzyme tryptophan synthase [130]. Bacterial and viral infection agents can be targeted by looking at proteins common to them.…”

Mycobacterium tuberculosis: Surviving and Indulging in an Unwelcoming Host

“…Amino acid biosynthetic pathways have always been at the heart of bacterial survival and pathogenesis. Arginine biosynthetic pathway in particular is known to be essential for Mtb virulence and several efforts are in line to better understand the key players of this pathway . Recently, we have identified a potential anti‐tubercular agent, Pranlukast, that targets the arginine biosynthesis in Mtb, thereby attenuating the pathogen survival in the mice models of tuberculosis.…”

“…Recently, we have identified a potential anti‐tubercular agent, Pranlukast, that targets the arginine biosynthesis in Mtb, thereby attenuating the pathogen survival in the mice models of tuberculosis. Remarkably, Pranlukast also targets the leukotriene biosynthesis in the host, by inhibiting the 5‐lipoxygenase (5‐LO) signalling . Such dual‐targeting mechanisms, wherein the pathogen and its host directed strategies are targeted simultaneously, will surely improve the therapeutic outcome of anti‐tubercular drugs in due course.…”