title: Zinc disrupts central carbon metabolism and capsule biosynthesis in Streptococcus pyogenes.
abstract: Neutrophils release free zinc to eliminate the phagocytosed bacterial pathogen Streptococcus pyogenes (Group A Streptococcus; GAS). In this study, we investigated the mechanisms underpinning zinc toxicity towards this human pathogen, responsible for diseases ranging from pharyngitis and impetigo, to severe invasive infections. Using the globally-disseminated M1T1 GAS strain, we demonstrate that zinc stress impairs glucose metabolism through the inhibition of the glycolytic enzymes phosphofructokinase and glyceraldehyde-3-phosphate dehydrogenase. In the presence of zinc, a metabolic shift to the tagatose-6-phosphate pathway allows conversion of D-galactose to dihydroxyacetone phosphate and glyceraldehyde phosphate, partially bypassing impaired glycolytic enzymes to generate pyruvate. Additionally, zinc inhibition of phosphoglucomutase results in decreased capsule biosynthesis. These data indicate that zinc exerts it toxicity via mechanisms that inhibit both GAS central carbon metabolism and virulence pathways.
authors.affiliation: School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, St. Lucia 4072, Australia.
authors.forename: Cheryl-lynn Y
authors.initials: CL
authors.lastname: Ong
authors.affiliation: School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, St. Lucia 4072, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Walker
authors.affiliation: School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, St. Lucia 4072, Australia.
authors.forename: Alastair G
authors.initials: AG
authors.lastname: McEwan
mesh_terms: D016667:Bacterial Capsules / Q000378:metabolism*; D002244:Carbon / Q000378:metabolism*; D005690:Galactose / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D006820:Hyaluronic Acid / Q000096:biosynthesis; D053858:Metabolic Networks and Pathways; D013290:Streptococcal Infections / Q000382:microbiology*; D013297:Streptococcus pyogenes / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D015032:Zinc / Q000633:toxicity*
chemical_list: D002244:Carbon; D006820:Hyaluronic Acid; D005947:Glucose; D015032:Zinc; D005690:Galactose