BACKGROUND: Tuberculosis (TB) ranks alongside the human immunodeficiency virus (HIV) as cause of death due to an infectious disease. Recently, host-targeted therapies (HDT) have gained attention as a means to shorten the course of treatment of drug-sensitive TB, improve treatment outcomes of drug-resistant TB and generally improve the efficacy and preserve or restore lung architecture of TB patients. It has been suggested that supplementing anti-TB therapy with host response modulators will augment standard TB treatment by overcoming antibiotic resistance in pathogenic strains of Mycobacterium tuberculosis (Mtb) and related species, thus aiding in killing non-replicating bacilli. METHODS: The aim of this review is to examine pulmonary delivery strategies that can enhance the safety as well as efficacy of HDT against pulmonary TB. We reviewed literature in the public domain and revisited our own results on inhaled HDT to arrive at broad conclusions. RESULTS: HDT can be viewed as a strategy to evoke one or more of the following macrophage responses: (i) soluble, intracellular factors such as free radicals and antimicrobial peptides; (ii) soluble extracellular signals like cytokines, chemokines, prostaglandins, lipids, etc.; (iii) organelles and assemblies such as phagolysosomes or the inflammasome; (iv) Autophagy, via mTOR/S6 Kinase; and (v) apoptosis via caspases, bcr/abl products, etc. All of these may be optimally addressed using drugs approved for other uses. CONCLUSION: Deployment of HDT in TB may be optimally achieved through macrophage-targeted inhaled delivery systems.
BACKGROUND:Tuberculosis (TB) ranks alongside the human immunodeficiency virus (HIV) as cause of death due to an infectious disease. Recently, host-targeted therapies (HDT) have gained attention as a means to shorten the course of treatment of drug-sensitive TB, improve treatment outcomes of drug-resistant TB and generally improve the efficacy and preserve or restore lung architecture of TB patients. It has been suggested that supplementing anti-TB therapy with host response modulators will augment standard TB treatment by overcoming antibiotic resistance in pathogenic strains of Mycobacterium tuberculosis (Mtb) and related species, thus aiding in killing non-replicating bacilli. METHODS: The aim of this review is to examine pulmonary delivery strategies that can enhance the safety as well as efficacy of HDT against pulmonary TB. We reviewed literature in the public domain and revisited our own results on inhaled HDT to arrive at broad conclusions. RESULTS: HDT can be viewed as a strategy to evoke one or more of the following macrophage responses: (i) soluble, intracellular factors such as free radicals and antimicrobial peptides; (ii) soluble extracellular signals like cytokines, chemokines, prostaglandins, lipids, etc.; (iii) organelles and assemblies such as phagolysosomes or the inflammasome; (iv) Autophagy, via mTOR/S6 Kinase; and (v) apoptosis via caspases, bcr/abl products, etc. All of these may be optimally addressed using drugs approved for other uses. CONCLUSION: Deployment of HDT in TB may be optimally achieved through macrophage-targeted inhaled delivery systems.
Authors: Christopher R M Asquith; Neil Fleck; Chad D Torrice; Daniel J Crona; Christoph Grundner; William J Zuercher Journal: Bioorg Med Chem Lett Date: 2019-07-10 Impact factor: 2.823