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Purpose: Mycobacterium tuberculosis (Mtb) inhibits host defense mechanisms, including autophagy. We investigated particles containing rapamycin (RAP) alone or in combination with isoniazid (INH) and rifabutin (RFB) for: targeting lung macrophages on inhalation; inducing autophagy; and killing macrophage-resident Mtb and/or augmenting anti-tuberculosis (TB) drugs., Methods: PLGA and drugs were spray-dried. Pharmacokinetics, partial biodistribution (LC-MS/MS) and efficacy (colony forming units, qPCR, acid fast staining, histopathology) in mice following dry powder inhalation were evaluated., Results: Aerodynamic diameters of formulations were 0.7-4.7 μm. Inhaled particles reached deep lungs and were phagocytosed by alveolar macrophages, yielding AUC0-48 of 102 compared to 0.1 μg/ml × h obtained with equivalent intravenous dose. RAP particles induced more autophagy in Mtb-infected macrophages than solutions. Inhaled particles containing RAP alone in daily, alternate-day and weekly dosing regimens reduced bacterial burden in lungs and spleens, inducing autophagy and phagosome-lysosome fusion. Inhalation of particles containing RAP with INH and RFB cleared the lungs and spleens of culturable bacteria., Conclusions: Targeting a potent autophagy-inducing agent to airway and lung macrophages alone is feasible, but not sufficient to eliminate Mtb. Combination of macrophage-targeted inhaled RAP with classical anti-TB drugs contributes to restoring tissue architecture and killing Mtb.

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.