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Subcellular antibiotic visualization reveals a dynamic drug reservoir in infected macrophages

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Science  28 Jun 2019:
Vol. 364, Issue 6447, pp. 1279-1282
DOI: 10.1126/science.aat9689

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Lipid droplets help anti-TB drug efficacy

Improving chemotherapies against intracellular pathogens requires understanding how antibiotic distribution within infected cells affects efficacy. Greenwood et al. developed an approach to visualize antibiotics in human macrophages infected with the tubercle bacillus (see the Perspective by Smith and Aldridge). They showed that the antitubercular (anti-TB) drug bedaquiline accumulated in host lipid droplets. Lipid droplets seemed to act as an antibiotic reservoir that could be transferred to bacteria during host lipid consumption. Indeed, alterations in host lipid droplet content affected the anti-TB activity of bedaquiline against intracellular bacilli.

Science, this issue p. 1279; see also p. 1234

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.

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