Abstract
S. aureus is classified as a serious threat pathogen and is a priority that guides the discovery and development of new antibiotics. Despite growing knowledge of S. aureus metabolic capabilities, our understanding of its systems-level responses to different media types remains incomplete. Here, we develop a manually reconstructed genome-scale model (GEM-PRO) of metabolism with 3D protein structures for S. aureus USA300 str. JE2 containing 854 genes, 1,440 reactions, 1,327 metabolites and 673 3-dimensional protein structures. Computations were in 85% agreement with gene essentiality data from random barcode transposon site sequencing (RB-TnSeq) and 68% agreement with experimental physiological data. Comparisons of computational predictions with experimental observations highlight: 1) cases of non-essential biomass precursors; 2) metabolic genes subject to transcriptional regulation involved in Staphyloxanthin biosynthesis; 3) the essentiality of purine and amino acid biosynthesis in synthetic physiological media; and 4) a switch to aerobic fermentation upon exposure to extracellular glucose elucidated as a result of integrating time-course of quantitative exo-metabolomics data. An up-to-date GEM-PRO thus serves as a knowledge-based platform to elucidate S. aureus’ metabolic response to its environment.
Highlights
Methicillin-resistant Staphylococcus aureus (MRSA) USA300 strains have emerged as the predominant cause of community-associated infections in the United States, Canada, and Europe [1]
We followed an established workflow for the reconstruction of genome-scale metabolic networks [15] to curate and update the most recent genome-scale model (GEM) of S. aureus [11] with new content
We found that growth could be successfully simulated in silico on chemically defined medium (CDM), CDMG, and CDMgal, but that iron supplementation was required for growth on SNM3 and supplementation with zinc and molybdate was required for CDMG2
Summary
Methicillin-resistant Staphylococcus aureus (MRSA) USA300 strains have emerged as the predominant cause of community-associated infections in the United States, Canada, and Europe [1]. Today in the United States more deaths are attributed to MRSA infections than to HIV/ AIDS [2,3]. USA300 was first isolated in September, 2000, and has been implicated in wideranging and epidemiologically unassociated outbreaks of skin and soft tissue infections in healthy individuals [4]. Many efforts are geared towards designing new antibiotic regimens to combat MRSA. These endeavors are impaired by the lack of replicability in antibiotic potency and bioactivity across different media [7]. Little is known about the systems-level effects of the nutritional environment on S. aureus growth and metabolism
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