(633f) Multi-Faceted Analysis Reveals the Metabolic Underpinnings of Overflow Metabolism in the Pathogenic Staphylococcus Aureus

Staphylococcus aureus is a dangerous human pathogen that infects approximately 20% of the world population. Furthermore, it has evolved multiple antibiotic-resistant strains making it difficult to treat with conventional medications. Experimental evidence has shown that unlike other pathogens, S. aureus performs overflow metabolism even during relatively low growth rates, indicating a potential bottleneck in the respiratory pathway. In this work, a multi-faceted modeling approach was used to investigate S. aureus’s metabolism. First, a thermodynamic analysis of the respiratory pathway was conducted to identify metabolic bottlenecks that compromise the pathway’s efficiency. Incorporation of these findings into a genome-scale metabolic model of S. aureus revealed that this leads to significant changes in central metabolism and has important implications for overflow metabolism. Furthermore, transcriptomic data from 7 distinct strains revealed that activity through the electron transport chain is affected my membrane-crowding effects during exponential growth. Finally, a coarse-grained analysis based on optimal resource allocation revealed that metabolically induced changes in the efficiency of the respiratory pathway has direct effects on overflow behavior.