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

Area of Science:

• Microbiology
• Pharmacology
• Immunology

Background:

• Tuberculosis treatment requires novel interventions targeting Mycobacterium tuberculosis (Mtb) pathogenesis.
• Existing therapies are insufficient against Mtb.
• Need for new drugs to combat intracellular Mtb survival and host-pathogen interactions.

Purpose of the Study:

• Identify novel therapeutic agents against Mtb.
• Investigate Pranlukast (PRK) as an inhibitor of Mtb's Ornithine acetyltransferase (MtArgJ).
• Evaluate PRK's efficacy in vitro and in vivo, and its impact on host signaling.

Main Methods:

• Screening for inhibitors of Mtb's Ornithine acetyltransferase (MtArgJ).
• In vitro assays assessing Mtb survival (free and macrophage-internalized).
• In vivo studies using Mtb-infected mice treated with PRK and rifampicin.
• Analysis of 5-lipoxygenase (5-LO) signaling in infected macrophages.

Main Results:

• Pranlukast (PRK) identified as a novel allosteric inhibitor of MtArgJ.
• PRK significantly reduced Mtb survival in vitro and in macrophages.
• PRK demonstrated enhanced efficacy when combined with standard drugs.
• PRK treatment decreased Mtb burden and granulomas in mouse lungs.
• PRK modulated 5-LO signaling in infected macrophages.

Conclusions:

• PRK targets both Mtb and host pro-survival signaling, acting as a dual-edged therapeutic agent.
• PRK shows significant in vitro and in vivo efficacy against Mtb.
• As an FDA-approved drug, PRK holds promise for advanced tuberculosis combination therapies.