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Pyruvate cycle increases aminoglycoside efficacy and provides respiratory energy in bacteria.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Feb 13; Vol. 115 (7), pp. E1578-E1587. Date of Electronic Publication: 2018 Jan 30. - Publication Year :
- 2018
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Abstract
- The emergence and ongoing spread of multidrug-resistant bacteria puts humans and other species at risk for potentially lethal infections. Thus, novel antibiotics or alternative approaches are needed to target drug-resistant bacteria, and metabolic modulation has been documented to improve antibiotic efficacy, but the relevant metabolic mechanisms require more studies. Here, we show that glutamate potentiates aminoglycoside antibiotics, resulting in improved elimination of antibiotic-resistant pathogens. When exploring the metabolic flux of glutamate, it was found that the enzymes that link the phosphoenolpyruvate (PEP)-pyruvate-AcCoA pathway to the TCA cycle were key players in this increased efficacy. Together, the PEP-pyruvate-AcCoA pathway and TCA cycle can be considered the pyruvate cycle (P cycle). Our results show that inhibition or gene depletion of the enzymes in the P cycle shut down the TCA cycle even in the presence of excess carbon sources, and that the P cycle operates routinely as a general mechanism for energy production and regulation in Escherichia coli and Edwardsiella tarda These findings address metabolic mechanisms of metabolite-induced potentiation and fundamental questions about bacterial biochemistry and energy metabolism.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Citric Acid Cycle drug effects
Energy Metabolism drug effects
Phosphoenolpyruvate metabolism
Aminoglycosides pharmacology
Anti-Bacterial Agents pharmacology
Edwardsiella tarda drug effects
Edwardsiella tarda metabolism
Escherichia coli drug effects
Escherichia coli metabolism
Pyruvic Acid metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 115
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 29382755
- Full Text :
- https://doi.org/10.1073/pnas.1714645115