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Host nutrient milieu drives an essential role for aspartate biosynthesis during invasive Staphylococcus aureus infection.

ABSTRACT: The bacterial pathogen Staphylococcus aureus is capable of infecting a broad spectrum of host tissues, in part due to flexibility of metabolic programs. S. aureus, like all organisms, requires essential biosynthetic intermediates to synthesize macromolecules. We therefore sought to determine the metabolic pathways contributing to synthesis of essential precursors during invasive S. aureus infection. We focused specifically on staphylococcal infection of bone, one of the most common sites of invasive S. aureus infection and a unique environment characterized by dynamic substrate accessibility, infection-induced hypoxia, and a metabolic profile skewed toward aerobic glycolysis. Using a murine model of osteomyelitis, we examined survival of S. aureus mutants deficient in central metabolic pathways, including glycolysis, gluconeogenesis, the tricarboxylic acid (TCA) cycle, and amino acid synthesis/catabolism. Despite the high glycolytic demand of skeletal cells, we discovered that S. aureus requires glycolysis for survival in bone. Furthermore, the TCA cycle is dispensable for survival during osteomyelitis, and S. aureus instead has a critical need for anaplerosis. Bacterial synthesis of aspartate in particular is absolutely essential for staphylococcal survival in bone, despite the presence of an aspartate transporter, which we identified as GltT and confirmed biochemically. This dependence on endogenous aspartate synthesis derives from the presence of excess glutamate in infected tissue, which inhibits aspartate acquisition by S. aureus Together, these data elucidate the metabolic pathways required for staphylococcal infection within bone and demonstrate that the host nutrient milieu can determine essentiality of bacterial nutrient biosynthesis pathways despite the presence of dedicated transporters.

SUBMITTER: Potter AD

PROVIDER: S-EPMC7275739 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Host nutrient milieu drives an essential role for aspartate biosynthesis during invasive Staphylococcus aureus infection.

Potter Aimee D AD Butrico Casey E CE Ford Caleb A CA Curry Jacob M JM Trenary Irina A IA Tummarakota Srivarun S SS Hendrix Andrew S AS Young Jamey D JD Cassat James E JE

Proceedings of the National Academy of Sciences of the United States of America 20200515 22

The bacterial pathogen Staphylococcus aureus is capable of infecting a broad spectrum of host tissues, in part due to flexibility of metabolic programs. S. aureus, like all organisms, requires essential biosynthetic intermediates to synthesize macromolecules. We therefore sought to determine the metabolic pathways contributing to synthesis of essential precursors during invasive S. aureus infection. We focused specifically on staphylococcal infection of bone, one of the most ...[more]

PMID: 32414924

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Project description:Staphylococcus aureus is a human pathogen, and S. aureus bacteremia can cause serious problems in humans. To identify the genes required for bacterial growth in calf serum (CS), a library of S. aureus mutants with randomly inserted transposons were analyzed for growth in CS, and the aspartate semialdehyde dehydrogenase (asd)-inactivated mutant exhibited significantly reduced growth in CS compared with the wild type (WT). The mutant also exhibited significantly reduced growth in medium, mimicking the concentrations of amino acids and glucose in CS. Asd is an essential enzyme for the biosynthesis of lysine, methionine, and threonine from aspartate. We constructed inactivated mutants of the genes for lysine (lysA), methionine (metE), and threonine (thrC) biosynthesis and found that the inactivated mutants of lysA and thrC exhibited significantly lower growth in CS than the WT, but the growth of the metE mutant was similar to that of the WT. The reduced growth of the asd mutant was recovered by addition of 100 ?g/ml lysine and threonine in CS. These results suggest that S. aureus requires lysine and threonine biosynthesis to grow in CS. On the other hand, the asd-, lysA-, metE-, and thrC-inactivated mutants exhibited significantly reduced growth in mouse serum compared with the WT. In mouse bacteremia experiments, the asd-, lysA-, metE-, and thrC-inactivated mutants exhibited attenuated virulence compared with WT infection. In conclusion, our results suggest that the biosynthesis of de novo aspartate family amino acids, especially lysine and threonine, is important for staphylococcal bloodstream infection.Studying the growth of bacteria in blood is important for understanding its pathogenicity in the host. Staphylococcus aureus sometimes causes bacteremia or sepsis. However, the factors responsible for S. aureus growth in the blood are not well understood. In this study, using a library of 2,914 transposon-insertional mutants in the S. aureus MW2 strain, we identified the factors responsible for bacterial growth in CS. We found that inactivation of the lysine and threonine biosynthesis genes led to deficient growth in CS. However, the inactivation of these genes did not affect S. aureus growth in general medium. Because the concentration of amino acids in CS is low compared to that in general bacterial medium, our results suggest that lysine and threonine biosynthesis is important for the growth of S. aureus in CS. Our findings provide new insights for S. aureus adaptation in the host and for understanding the pathogenesis of bacteremia.

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Host nutrient milieu drives an essential role for aspartate biosynthesis during invasive Staphylococcus aureus infection.

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Host nutrient milieu drives an essential role for aspartate biosynthesis during invasive <i>Staphylococcus aureus</i> infection.

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Host nutrient milieu drives an essential role for aspartate biosynthesis during invasive Staphylococcus aureus infection.

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Host nutrient milieu drives an essential role for aspartate biosynthesis during invasive &lt;i&gt;Staphylococcus aureus&lt;/i&gt; infection.

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OmicsDI is part of the ELIXIR infrastructure

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Host nutrient milieu drives an essential role for aspartate biosynthesis during invasive <i>Staphylococcus aureus</i> infection.