Understanding and Sensitizing Density-Dependent Persistence to Quinolone Antibiotics
| Autor: | Saloni R. Jain, Michael A. Lobritz, Arnaud Gutierrez, Meagan Hamblin, James J. Collins, Prerna Bhargava |
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| Přispěvatelé: | 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. |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.drug_class Antibiotics Cell Respiration Oxidative phosphorylation Microbial Sensitivity Tests Quinolones medicine.disease_cause Oxidative Phosphorylation Microbiology 03 medical and health sciences Drug Resistance Bacterial medicine Molecular Biology Escherichia coli biology Bacteria Catabolism Mycobacterium smegmatis Cell Biology Bacterial Infections biology.organism_classification Quinolone Carbon Anti-Bacterial Agents Oxygen 030104 developmental biology Staphylococcus aureus |
| Zdroj: | Elsevier |
| ISSN: | 1097-4164 |
| Popis: | 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) |
| Databáze: | OpenAIRE |
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