Understanding and Sensitizing Density-Dependent Persistence to Quinolone Antibiotics
Physiologic and environmental factors can modulate antibiotic activity and thus pose a significant challenge to antibiotic treatment. The quinolone class of antibiotics, which targets bacterial topoisomerases, fails to kill bacteria that have grown to high density; however, the mechanistic basis for...
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| Format: | Article |
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Elsevier BV
2018
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| Online Access: | http://hdl.handle.net/1721.1/117581 https://orcid.org/0000-0002-9512-0659 https://orcid.org/0000-0002-0712-3383 https://orcid.org/0000-0002-5560-8246 |
| _version_ | 1826199100180135936 |
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| author | Hamblin, Meagan Gutierrez, Arnaud Jain, Saloni R. Saluja, Prerna Bhargava Lobritz, Michael Andrew Collins, James J. |
| author2 | Institute for Medical Engineering and Science |
| author_facet | Institute for Medical Engineering and Science Hamblin, Meagan Gutierrez, Arnaud Jain, Saloni R. Saluja, Prerna Bhargava Lobritz, Michael Andrew Collins, James J. |
| author_sort | Hamblin, Meagan |
| collection | MIT |
| description | Physiologic and environmental factors can modulate antibiotic activity and thus pose a significant challenge to antibiotic treatment. The quinolone class of antibiotics, which targets bacterial topoisomerases, fails to kill bacteria that have grown to high density; however, the mechanistic basis for this persistence is unclear. Here, we show that exhaustion of the metabolic inputs that couple carbon catabolism to oxidative phosphorylation is a primary cause of growth phase-dependent persistence to quinolone antibiotics. Supplementation of stationary-phase cultures with glucose and a suitable terminal electron acceptor to stimulate respiratory metabolism is sufficient to sensitize cells to quinolone killing. Using this approach, we successfully sensitize high-density populations of Escherichia coli, Staphylococcus aureus, and Mycobacterium smegmatis to quinolone antibiotics. Our findings link growth-dependent quinolone persistence to discrete impairments in respiratory metabolism and identify a strategy to kill non-dividing bacteria. Gutierrez et al. show that activation of cellular respiration is sufficient to sensitize antibiotic refractory bacteria at high densities to drugs targeting DNA topoisomerases. This suggests that the nutrient environment and metabolic state are key components of bacterial persistence phenotypes. Keywords: quinolones; drug persistence; antibiotic; oxidative phosphorylation |
| first_indexed | 2024-09-23T11:14:43Z |
| format | Article |
| id | mit-1721.1/117581 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T11:14:43Z |
| publishDate | 2018 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1175812022-10-01T02:19:09Z Understanding and Sensitizing Density-Dependent Persistence to Quinolone Antibiotics Hamblin, Meagan Gutierrez, Arnaud Jain, Saloni R. Saluja, Prerna Bhargava Lobritz, Michael Andrew Collins, James J. Institute for Medical Engineering and Science Massachusetts Institute of Technology. Department of Biological Engineering Gutierrez, Arnaud Jain, Saloni R. Saluja, Prerna Bhargava Lobritz, Michael Andrew Collins, James J. Physiologic and environmental factors can modulate antibiotic activity and thus pose a significant challenge to antibiotic treatment. The quinolone class of antibiotics, which targets bacterial topoisomerases, fails to kill bacteria that have grown to high density; however, the mechanistic basis for this persistence is unclear. Here, we show that exhaustion of the metabolic inputs that couple carbon catabolism to oxidative phosphorylation is a primary cause of growth phase-dependent persistence to quinolone antibiotics. Supplementation of stationary-phase cultures with glucose and a suitable terminal electron acceptor to stimulate respiratory metabolism is sufficient to sensitize cells to quinolone killing. Using this approach, we successfully sensitize high-density populations of Escherichia coli, Staphylococcus aureus, and Mycobacterium smegmatis to quinolone antibiotics. Our findings link growth-dependent quinolone persistence to discrete impairments in respiratory metabolism and identify a strategy to kill non-dividing bacteria. Gutierrez et al. show that activation of cellular respiration is sufficient to sensitize antibiotic refractory bacteria at high densities to drugs targeting DNA topoisomerases. This suggests that the nutrient environment and metabolic state are key components of bacterial persistence phenotypes. Keywords: quinolones; drug persistence; antibiotic; oxidative phosphorylation Defense Threat Reduction Agency (DTRA) (Grant HDTRA1-15-1-0051) 2018-08-28T15:11:14Z 2018-08-28T15:11:14Z 2017-12 2017-10 2018-08-27T18:50:09Z Article http://purl.org/eprint/type/JournalArticle 1097-2765 1097-4164 http://hdl.handle.net/1721.1/117581 Gutierrez, Arnaud et al. “Understanding and Sensitizing Density-Dependent Persistence to Quinolone Antibiotics.” Molecular Cell 68, 6 (December 2017): 1147–1154 © 2017 The Authors https://orcid.org/0000-0002-9512-0659 https://orcid.org/0000-0002-0712-3383 https://orcid.org/0000-0002-5560-8246 http://dx.doi.org/10.1016/J.MOLCEL.2017.11.012 Molecular Cell Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV Elsevier |
| spellingShingle | Hamblin, Meagan Gutierrez, Arnaud Jain, Saloni R. Saluja, Prerna Bhargava Lobritz, Michael Andrew Collins, James J. Understanding and Sensitizing Density-Dependent Persistence to Quinolone Antibiotics |
| title | Understanding and Sensitizing Density-Dependent Persistence to Quinolone Antibiotics |
| title_full | Understanding and Sensitizing Density-Dependent Persistence to Quinolone Antibiotics |
| title_fullStr | Understanding and Sensitizing Density-Dependent Persistence to Quinolone Antibiotics |
| title_full_unstemmed | Understanding and Sensitizing Density-Dependent Persistence to Quinolone Antibiotics |
| title_short | Understanding and Sensitizing Density-Dependent Persistence to Quinolone Antibiotics |
| title_sort | understanding and sensitizing density dependent persistence to quinolone antibiotics |
| url | http://hdl.handle.net/1721.1/117581 https://orcid.org/0000-0002-9512-0659 https://orcid.org/0000-0002-0712-3383 https://orcid.org/0000-0002-5560-8246 |
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