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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Schwarz, Eric G. Yang, Jason H. Porter, Caroline B. M. Gutierrez, Arnaud Dwyer, Daniel J. Collins, James J. Lobritz, Michael A. Belenky, Peter Khalil, Ahmad S. |
| Description | Author Affiliation: Lobritz MA ( Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115); Belenky P ( Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912); Porter CB ( Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139); Gutierrez A ( Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139); Yang JH ( Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139); Schwarz EG ( Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA 02215); Dwyer DJ ( Department of Cell Biology and Molecular Genetics, Institute for Physical Science and Technology, Department of Biomedical Engineering, and Maryland Pathogen Research Institute, University of Maryland, College Park, MD 20742); Khalil AS ( Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115); Collins JJ ( Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115); |
| Abstract | Bacteriostatic and bactericidal antibiotic treatments result in two fundamentally different phenotypic outcomes--the inhibition of bacterial growth or, alternatively, cell death. Most antibiotics inhibit processes that are major consumers of cellular energy output, suggesting that antibiotic treatment may have important downstream consequences on bacterial metabolism. We hypothesized that the specific metabolic effects of bacteriostatic and bactericidal antibiotics contribute to their overall efficacy. We leveraged the opposing phenotypes of bacteriostatic and bactericidal drugs in combination to investigate their activity. Growth inhibition from bacteriostatic antibiotics was associated with suppressed cellular respiration whereas cell death from most bactericidal antibiotics was associated with accelerated respiration. In combination, suppression of cellular respiration by the bacteriostatic antibiotic was the dominant effect, blocking bactericidal killing. Global metabolic profiling of bacteriostatic antibiotic treatment revealed that accumulation of metabolites involved in specific drug target activity was linked to the buildup of energy metabolites that feed the electron transport chain. Inhibition of cellular respiration by knockout of the cytochrome oxidases was sufficient to attenuate bactericidal lethality whereas acceleration of basal respiration by genetically uncoupling ATP synthesis from electron transport resulted in potentiation of the killing effect of bactericidal antibiotics. This work identifies a link between antibiotic-induced cellular respiration and bactericidal lethality and demonstrates that bactericidal activity can be arrested by attenuated respiration and potentiated by accelerated respiration. Our data collectively show that antibiotics perturb the metabolic state of bacteria and that the metabolic state of bacteria impacts antibiotic efficacy. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 27 |
| Volume Number | 112 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2015-07-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Anti-Bacterial Agents Pharmacology Bacteria Drug Effects Microbial Viability Oxygen Consumption Adenosine Triphosphate Biosynthesis Classification Genetics Metabolism Bacterial Physiological Phenomena Drug Interactions Escherichia Coli Growth & Development Metabolome Metabolomics Microbial Sensitivity Tests Mutation Staphylococcus Aureus Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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