Abstract
Tuberculosis, caused by the intracellular pathogen Mycobacterium tuberculosis, remains the world's deadliest infectious disease. Sterilizing chemotherapy requires at least 6 months of multidrug therapy. Difficulty visualizing the subcellular localization of antibiotics in infected host cells means that it is unclear whether antibiotics penetrate all mycobacteria-containing compartments in the cell. Here, we combined correlated light, electron, and ion microscopy to image the distribution of bedaquiline in infected human macrophages at submicrometer resolution. Bedaquiline accumulated primarily in host cell lipid droplets, but heterogeneously in mycobacteria within a variety of intracellular compartments. Furthermore, lipid droplets did not sequester antibiotic but constituted a transferable reservoir that enhanced antibacterial efficacy. Thus, strong lipid binding facilitated drug trafficking by host organelles to an intracellular target during antimicrobial treatment.
Highlights
Tuberculosis, caused by the intracellular pathogen Mycobacterium tuberculosis, remains the world’s deadliest infectious disease
BDQ was found in Mycobacterium tuberculosis (Mtb) in a variety of intracellular environments including in a membranous vacuole and a lysing necrotic macrophage (Fig. 1, A and B), a known mycobacterial niche [1]
We observed Mtb interacting with host lipid droplets (LD) as previously reported [10], and found the LD to be highly enriched with antibiotic (Fig. 1C)
Summary
Tuberculosis, caused by the intracellular pathogen Mycobacterium tuberculosis, remains the world’s deadliest infectious disease. To characterise the intracellular distribution of BDQ, we infected human monocyte-derived macrophages (hMDM) with Mtb for 48 h, giving bacteria time to enter multiple sub-cellular compartments [1]. BDQ accumulated heterogeneously in Mtb within macrophages, even between neighbouring bacteria (Fig. 1A).
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