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Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):E1578-E1587. doi: 10.1073/pnas.1714645115. Epub 2018 Jan 30.

Pyruvate cycle increases aminoglycoside efficacy and provides respiratory energy in bacteria.

Author information

1
Center for Proteomics and Metabolomics, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, University City, Guangzhou 510006, People's Republic of China.
2
Center for Proteomics and Metabolomics, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, University City, Guangzhou 510006, People's Republic of China; pxuanx@sysu.edu.cn peng26@sysu.edu.cn.
3
Laboratory for Marine Fisheries Science and Food Production Processes, Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266071, People's Republic of China.
4
Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, Sun Yat-sen University, University City, Guangzhou 510006, People's Republic of China.
5
Department of Respiratory Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, People's Republic of China.

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.

KEYWORDS:

P cycle; TCA cycle; antibiotic resistance; energy metabolism; metabolites

PMID:
29382755
PMCID:
PMC5816162
DOI:
10.1073/pnas.1714645115
[Indexed for MEDLINE]
Free PMC Article

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