Pyruvate Abundance Confounds Aminoglycoside Killing of Multidrug-Resistant Bacteria via Glutathione Metabolism
Jiao Xiang,
Si-qi Tian,
Shi-wen Wang,
Ying-li Liu,
Hui Li,
Bo Peng
Affiliations
Jiao Xiang
State Key Laboratory of Bio-Control, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes,
School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen University, Guangzhou 510275, China.
Si-qi Tian
State Key Laboratory of Bio-Control, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes,
School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen University, Guangzhou 510275, China.
Shi-wen Wang
State Key Laboratory of Bio-Control, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes,
School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen University, Guangzhou 510275, China.
Ying-li Liu
State Key Laboratory of Bio-Control, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes,
School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen University, Guangzhou 510275, China.
Hui Li
State Key Laboratory of Bio-Control, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes,
School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen University, Guangzhou 510275, China.
Bo Peng
State Key Laboratory of Bio-Control, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes,
School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen University, Guangzhou 510275, China.
To explore whether the metabolic state reprogramming approach may be used to explore previously unknown metabolic pathways that contribute to antibiotic resistance, especially those that have been neglected in previous studies, pyruvate reprogramming was performed to reverse the resistance of multidrug-resistant Edwardsiella tarda. Surprisingly, we identified a pyruvate-regulated glutathione system that occurs by boosting glycine, serine, and threonine metabolism. Moreover, cysteine and methionine metabolism played a key role in this reversal. This process involved pyruvate-depressed glutathione and pyruvate-promoted glutathione oxidation, which was attributed to the elevated glutathione peroxidase and depressed glutathione reductase that was inhibited by glycine. This regulation inhibited reactive oxygen species (ROS) degradation and thereby elevated ROS to eliminate E. tarda. Loss of metB, gpx, and gor of the metabolic pathways increased and decreased resistance, respectively, both in vitro and in vivo, thereby supporting the hypothesis of a pyruvate–cysteine–glutathione system/glycine–ROS metabolic pathway. The role of this metabolic pathway in drug resistance and reprogramming reversal was demonstrated in laboratory-evolved gentamicin-resistant E. tarda and other clinically isolated multidrug- and carbapenem-resistant pathogens. Thus, we reveal a less studied antibiotic resistance metabolic pathway along with the mechanisms involved in its reversal.