A Thermodynamic Bottleneck in the TCA Cycle Contributes to Acetate Overflow in Staphylococcus aureus

Authors

• Nabia Shahreen, University of Nebraska-Lincoln
• Jongsam Ahn, University of Nebraska Medical Center
• Adil Alsiyabi, University of Nebraska-Lincoln and University of Nizwa
• Niaz Bahar Chowdhury, University of Nebraska-Lincoln
• Dhananjay Shinde, University of Nebraska Medical Center
• Sujata S. Chaudhari, University of Nebraska Medical Center
• Kenneth W. Bayles, University of Nebraska Medical Center
• Vinai C. Thomas, University of Nebraska Medical CenterFollow
• Rajib Saha, University of Nebraska-LincolnFollow

ORCID IDs

Shahreen https://orcid.org/0000-0002-6461-6184

Thomas https://orcid.org/0000-0002-7886-0727

Saha https://orcid.org/0000-0002-2974-0243

Date of this Version

2024

Document Type

Article

Citation

mSphere (2025) 10(1)

doi: 10.1128/msphere.00883-24

Comments

Open access

License: CC BY 4.0

Abstract

During aerobic growth, S. aureus relies on acetate overflow metabolism, a process where glucose is incompletely oxidized to acetate, for its bioenergetic needs. Acetate is not immediately captured as a carbon source and is excreted as waste by cells. The underlying factors governing acetate overflow in S. aureus have not been identified. Here, we show that acetate overflow is favored due to a thermodynamic bottleneck in the TCA cycle specifically involving the oxidation of succinate to fumarate by succinate dehydrogenase. This bottleneck reduces flux through the TCA cycle, making it more efficient for S. aureus to generate ATP via acetate overflow metabolism. Additionally, the protein allocation cost of maintaining ATP flux through the restricted TCA cycle is greater than that of acetate overflow metabolism. Finally, we show that the TCA cycle bottleneck provides S. aureus the flexibility to redirect carbon toward maintaining redox balance through lactate overflow when oxygen becomes limiting, albeit at the expense of ATP production through acetate overflow. Overall, our findings suggest that overflow metabolism offers S. aureus distinct bioenergetic advantages over a thermodynamically constrained TCA cycle, potentially supporting its commensal–pathogenic lifestyle.