Subcellular antibiotic visualization reveals a dynamic drug reservoir in infected macrophages

Daniel J. Greenwood, Mariana Silva Dos Santos, Song Huang, Matthew R. G. Russell, Lucy M. Collinson, James I. MacRae, Andy West, Haibo Jiang, Maximiliano G. Gutierrez

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1279-+
Number of pages22
JournalScience
Volume364
Issue number6447
DOIs
Publication statusPublished - 28 Jun 2019

Cite this

Greenwood, D. J., Dos Santos, M. S., Huang, S., Russell, M. R. G., Collinson, L. M., MacRae, J. I., ... Gutierrez, M. G. (2019). Subcellular antibiotic visualization reveals a dynamic drug reservoir in infected macrophages. Science, 364(6447), 1279-+. https://doi.org/10.1126/science.aat9689
Greenwood, Daniel J. ; Dos Santos, Mariana Silva ; Huang, Song ; Russell, Matthew R. G. ; Collinson, Lucy M. ; MacRae, James I. ; West, Andy ; Jiang, Haibo ; Gutierrez, Maximiliano G. / Subcellular antibiotic visualization reveals a dynamic drug reservoir in infected macrophages. In: Science. 2019 ; Vol. 364, No. 6447. pp. 1279-+.
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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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Greenwood, DJ, Dos Santos, MS, Huang, S, Russell, MRG, Collinson, LM, MacRae, JI, West, A, Jiang, H & Gutierrez, MG 2019, 'Subcellular antibiotic visualization reveals a dynamic drug reservoir in infected macrophages' Science, vol. 364, no. 6447, pp. 1279-+. https://doi.org/10.1126/science.aat9689

Subcellular antibiotic visualization reveals a dynamic drug reservoir in infected macrophages. / Greenwood, Daniel J.; Dos Santos, Mariana Silva; Huang, Song; Russell, Matthew R. G.; Collinson, Lucy M.; MacRae, James I.; West, Andy; Jiang, Haibo; Gutierrez, Maximiliano G.

In: Science, Vol. 364, No. 6447, 28.06.2019, p. 1279-+.

Research output: Contribution to journalArticle

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AU - Dos Santos, Mariana Silva

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AU - MacRae, James I.

AU - West, Andy

AU - Jiang, Haibo

AU - Gutierrez, Maximiliano G.

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AB - 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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Greenwood DJ, Dos Santos MS, Huang S, Russell MRG, Collinson LM, MacRae JI et al. Subcellular antibiotic visualization reveals a dynamic drug reservoir in infected macrophages. Science. 2019 Jun 28;364(6447):1279-+. https://doi.org/10.1126/science.aat9689