The methylglyoxal pathway is a sink for glutathione in Salmonella experiencing oxidative stress

• Published in: PLoS pathogens Vol. 19; no. 6; p. e1011441
• Main Authors: Kant, Sashi, Liu, Lin, Vazquez-Torres, Andres
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.06.2023; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Antimicrobial agents; Biology and Life Sciences; Control; Cytotoxicity; Dextrose; Enzymatic activity; Genes; Glucose; Glucose metabolism; Glutathione; Glutathione - metabolism; Glycolysis; Health aspects; Hydrogen peroxide; Hydrogen Peroxide - metabolism; Identification and classification; Macrophages; Medicine and Health Sciences; Metabolism; Mice; Molecular modelling; NAD(P)H oxidase; NADPH Oxidases - metabolism; Oxidase; Oxidases; Oxidation; Oxidation resistance; Oxidative Stress; Oxygen; Peroxides; Phagocytes; Phosphorylation; Physical Sciences; Properties; Pyruvaldehyde; Pyruvaldehyde - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; Respiration; Respiratory burst; Salmonella; Salmonella typhimurium - metabolism; Scientific equipment and supplies industry; Superoxide; Superoxides; Toxicity; United States
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1011441

Salmonella suffer the cytotoxicity of reactive oxygen species generated by the phagocyte NADPH oxidase in the innate host response. Periplasmic superoxide dismutases, catalases and hydroperoxidases detoxify superoxide and hydrogen peroxide (H2O2) synthesized in the respiratory burst of phagocytic cells. Glutathione also helps Salmonella combat the phagocyte NADPH oxidase; however, the molecular mechanisms by which this low-molecular-weight thiol promotes resistance of Salmonella to oxidative stress are currently unknown. We report herein that Salmonella undergoing oxidative stress transcriptionally and functionally activate the methylglyoxal pathway that branches off from glycolysis. Activation of the methylglyoxal pathway consumes a substantial proportion of the glutathione reducing power in Salmonella following exposure to H2O2. The methylglyoxal pathway enables Salmonella to balance glucose utilization with aerobic respiratory outputs. Salmonella take advantage of the metabolic flexibility associated with the glutathione-consuming methylglyoxal pathway to resist reactive oxygen species generated by the enzymatic activity of the phagocyte NADPH oxidase in macrophages and mice. Taken together, glutathione fosters oxidative stress resistance in Salmonella against the antimicrobial actions of the phagocyte NADPH oxidase by promoting the methylglyoxal pathway, an offshoot metabolic adaptation of glycolysis.