Subcellular antibiotic visualization reveals a dynamic drug reservoir in infected macrophages
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 t...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2019-06, Vol.364 (6447), p.1279-1282 |
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| creator | 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. |
| description | 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. |
| doi_str_mv | 10.1126/science.aat9689 |
| format | Article |
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G. ; Collinson, Lucy M. ; MacRae, James I. ; West, Andy ; Jiang, Haibo ; Gutierrez, Maximiliano G.</creator><creatorcontrib>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.</creatorcontrib><description>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.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.aat9689</identifier><identifier>PMID: 31249058</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Antibiotics ; Antiinfectives and antibacterials ; Antitubercular Agents - analysis ; Antitubercular Agents - pharmacokinetics ; Antitubercular Agents - pharmacology ; Bacilli ; Chemotherapy ; Communicable Diseases ; Compartments ; Diarylquinolines - analysis ; Diarylquinolines - pharmacokinetics ; Diarylquinolines - pharmacology ; Droplets ; Drug efficacy ; Effectiveness ; Humans ; Infectious diseases ; Intracellular ; Lipid Droplets - chemistry ; Lipid Droplets - metabolism ; Lipids ; Localization ; Macrophages ; Macrophages - chemistry ; Macrophages - metabolism ; Macrophages - microbiology ; Microscopy, Electron ; Mycobacterium tuberculosis ; Organelles ; Pathogens ; Tuberculosis</subject><ispartof>Science (American Association for the Advancement of Science), 2019-06, Vol.364 (6447), p.1279-1282</ispartof><rights>Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.</rights><rights>Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. 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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.</description><subject>Antibiotics</subject><subject>Antiinfectives and antibacterials</subject><subject>Antitubercular Agents - analysis</subject><subject>Antitubercular Agents - pharmacokinetics</subject><subject>Antitubercular Agents - pharmacology</subject><subject>Bacilli</subject><subject>Chemotherapy</subject><subject>Communicable Diseases</subject><subject>Compartments</subject><subject>Diarylquinolines - analysis</subject><subject>Diarylquinolines - pharmacokinetics</subject><subject>Diarylquinolines - pharmacology</subject><subject>Droplets</subject><subject>Drug efficacy</subject><subject>Effectiveness</subject><subject>Humans</subject><subject>Infectious diseases</subject><subject>Intracellular</subject><subject>Lipid Droplets - chemistry</subject><subject>Lipid Droplets - metabolism</subject><subject>Lipids</subject><subject>Localization</subject><subject>Macrophages</subject><subject>Macrophages - chemistry</subject><subject>Macrophages - metabolism</subject><subject>Macrophages - microbiology</subject><subject>Microscopy, Electron</subject><subject>Mycobacterium tuberculosis</subject><subject>Organelles</subject><subject>Pathogens</subject><subject>Tuberculosis</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkUFrGzEQhUVoSBwn555aFnpeR9KuVtKlUEyTFgw5JD0WMauddWTWK1fSGpJfHwW7pgWBQO-bNzN6hHxkdMEYb26jdThaXAAk3Sh9RmaMalFqTqsPZEZp1ZSKSnFJrmLcUJo1XV2Qy4rxWlOhZuT349RaHIZpgFDAmFzrfHK22Ls4weBeITk_FgH3CEMsoOheRthmvQvTOj9HDHvvQuHGfHq0CbtiCzb43TOsMV6T8z7X4c3xnpNfd9-flj_K1cP9z-W3VWlrRVPZay1k20gmK9H2yBlWTc006q5XnVDYad3mLdqWaV6jtLKWvIFOMZQgFLBqTr4efHdTu8XO4pgCDGYX3BbCi_HgzP_K6J7N2u-NpPkXa5ENvhwNgv8zYUxm46cw5pkN50JyrpRoMnV7oPKCMQbsTx0YNe95mGMe5phHrvj872An_m8AGfh0ADYx-XDSeSNrwVVdvQFOkZVt</recordid><startdate>20190628</startdate><enddate>20190628</enddate><creator>Greenwood, Daniel J.</creator><creator>Dos Santos, Mariana Silva</creator><creator>Huang, Song</creator><creator>Russell, Matthew R. 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G.</au><au>Collinson, Lucy M.</au><au>MacRae, James I.</au><au>West, Andy</au><au>Jiang, Haibo</au><au>Gutierrez, Maximiliano G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Subcellular antibiotic visualization reveals a dynamic drug reservoir in infected macrophages</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2019-06-28</date><risdate>2019</risdate><volume>364</volume><issue>6447</issue><spage>1279</spage><epage>1282</epage><pages>1279-1282</pages><issn>0036-8075</issn><eissn>1095-9203</eissn><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. 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| source | American Association for the Advancement of Science; MEDLINE |
| subjects | Antibiotics Antiinfectives and antibacterials Antitubercular Agents - analysis Antitubercular Agents - pharmacokinetics Antitubercular Agents - pharmacology Bacilli Chemotherapy Communicable Diseases Compartments Diarylquinolines - analysis Diarylquinolines - pharmacokinetics Diarylquinolines - pharmacology Droplets Drug efficacy Effectiveness Humans Infectious diseases Intracellular Lipid Droplets - chemistry Lipid Droplets - metabolism Lipids Localization Macrophages Macrophages - chemistry Macrophages - metabolism Macrophages - microbiology Microscopy, Electron Mycobacterium tuberculosis Organelles Pathogens Tuberculosis |
| title | Subcellular antibiotic visualization reveals a dynamic drug reservoir in infected macrophages |
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