(373f) Omics-Informed Metabolic Modeling of Staphylococcus Aureus Reveals Underlying Principles of Overflow Metabolism

Staphylococcus aureus is a gram-positive human pathogenic bacterium that causes a wide variety of diseases, ranging from severe skin infections to fatal pneumonia. Due to its high metabolic adaptability to antibiotics, some strains of S. aureus have developed antibiotic resistance, thereby making traditional treatments challenging. An interesting characteristic of S. aureus is that it performs overflow metabolism during exponential growth, despite respiration being the most efficient way to produce ATP. In this work, we examined this unusual phenomenon of S. aureus from a synergistic experimental and computational perspective. First, a thermodynamic analysis of the respiratory pathway revealed that the menaquinone-based succinate dehydrogenase reaction of TCA cycle is infeasible during aerobic growth on glucose but feasible during growth on acetate. Experimental omics data further verifies this observation. To better understand this metabolic mechanism, based on previously published genome-scale metabolic model (GEM) of S. aureus (Mazharul Islam et al., 2020), we reconstructed contextualized models of different growth phases of multiple strains (Δpyc, ΔcitZ, ΔsucA, ΔackA, ΔgudB, ΔndhA, ΔmenD, and ΔatpA) using transcriptomics data. These strains were selected for their potential in impacting key cellular processes such as carbon and nitrogen redirection pathways, cellular redox homeostasis, and overflow metabolism. A systems-level investigation of the metabolic landscape of these mutants pertinent to the overflow metabolism may connect this unusual metabolic trait of S. aureus to its antibiotic resistance. In this regard, flux variability, metabolic bottleneck, and shadow price analysis were conducted, and they showed significant differences in central metabolism across strains in exponential and stationary phase. Finally, these findings will be used to obtain regulatory points in this lethal bacterium’s metabolism that can be potential therapeutics.

Reference

Mazharul Islam, M., Thomas, V. C., Van Beek, M., Ahn, J. S., Alqarzaee, A. A., Zhou, C., Fey, P. D., Bayles, K. W., & Saha, R. (2020). An integrated computational and experimental study to investigate Staphylococcus aureus metabolism. Npj Systems Biology and Applications, 6(1), 1–13. https://doi.org/10.1038/s41540-019-0122-3