Targeting Intracellular Mycobacterium Tuberculosis by Exploiting Host-Pathogen Interactions

Abstract

Infinite combinations of complex interactions between host, pathogen, and environment generate considerable heterogeneity in the disease states of those infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). This high degree of disease heterogeneity makes TB particularly challenging to treat and necessitates lengthy treatment regimens. A better understanding of the factors that impact antibiotic activity (i.e. pharmacodynamics) and exposure (i.e pharmacokinetics) is needed to improve TB treatment. Here we investigated the effect of host immunity on mycobacterial respiration to provide a better understanding of how host pressures can affect the performance of antimycobacterial drugs. We show that cytochrome bd oxidase in Mtb is required for fitness in acidic environments like those found in the phagosome of IFNγ-activated macrophages. These acidic environments alter the respiratory requirements of Mtb consequently affecting the efficacy of respiratory inhibitors under these conditions, demonstrating a potential synergy between host immunity and drug PD. Separately, we conducted a proof-of-concept study using glucan lipid particles (GLPs) as a generalizable, inhalable drug delivery platform for antimycobacterial compounds. We aimed to alter the PK of existing TB antibiotics by creating formulations that better localize drugs to the site of infection, slow-release, and limit systemic drug exposure. GLPs can accommodate a variety of payloads, can be aerosolized, and are selectively taken up by macrophages. These qualities make them an attractive TB drug delivery platform. Using novel packaging techniques, we stably and efficiently loaded both first- and second-line TB therapeutics into GLPs. We show that intranasal delivery of GLP-encapsulated clofazimine reduced Mtb burden in vivo and increased drug retention in the lung. Together these studies highlight the multifactorial nature of drug performance in TB. Each of these studies focuses on the impact of the host on drug PK or PD whether by targeting drug delivery to immune cells or identifying critical interactions between immunity and bacterial physiology, respectively. This work provides insights and tools for future development of TB therapies.