The cellular esterase FrmB controls metabolic homeostasis and small colony variant formation in Staphylococcus aureus

Kelsey A O’Brien, Justin J Miller, R. Jeremy Johnson, Geoffrey C Hoops, Audrey R Odom John
2026 · doi:10.64898/2026.03.26.714663
preprint OA: closed CC-BY-ND-4.0
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Abstract

Staphylococcus aureus is a gram-positive bacterium that commonly colonizes the nasal passage, axilla, groin, and gastrointestinal tract of adults and adolescents. Although frequently nonpathogenic, S. aureus can infect most tissue types with clinical outcomes ranging from mild to fatal. The ability of S. aureus to persist and infect multiple body sites is driven largely by its metabolism. S. aureus can metabolize a wide range of niche-specific carbon sources, which contributes significantly to its persistence. Specifically, the utilization of glycolytic intermediates and pyruvate are associated with S. aureus bacterial burden and survival in the host. In this study, we establish the biological role of a serine hydrolase, FrmB, and evaluate its impact on S. aureus carbon metabolism. Using targeted metabolomics on S. aureus strains with and without FrmB, we find that FrmB is required for central carbon metabolic homeostasis. Mechanistically, we find that FrmB controls the enzymatic activity of the crucial rate-limiting enzyme, pyruvate dehydrogenase, which links glycolysis to the downstream tricarboxylic acid (TCA) cycle. Importantly, we find that the metabolic derangements in the absence of FrmB impact the ability of S. aureus to utilize pyruvate as a primary carbon source and reduce fitness. Finally, we demonstrate that FrmB is important for the formation of small colony variants (SCVs), a clinically relevant metabolic transition that is associated with chronic infection and antibiotic resistance.
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Abstract Staphylococcus aureus is a gram-positive bacterium that commonly colonizes the nasal passage, axilla, groin, and gastrointestinal tract of adults and adolescents. Although frequently nonpathogenic, S. aureus can infect most tissue types with clinical outcomes ranging from mild to fatal. The ability of S. aureus to persist and infect multiple body sites is driven largely by its metabolism. S. aureus can metabolize a wide range of niche-specific carbon sources, which contributes significantly to its persistence. Specifically, the utilization of glycolytic intermediates and pyruvate are associated with S. aureus bacterial burden and survival in the host. In this study, we establish the biological role of a serine hydrolase, FrmB, and evaluate its impact on S. aureus carbon metabolism. Using targeted metabolomics on S. aureus strains with and without FrmB, we find that FrmB is required for central carbon metabolic homeostasis. Mechanistically, we find that FrmB controls the enzymatic activity of the crucial rate-limiting enzyme, pyruvate dehydrogenase, which links glycolysis to the downstream tricarboxylic acid (TCA) cycle. Importantly, we find that the metabolic derangements in the absence of FrmB impact the ability of S. aureus to utilize pyruvate as a primary carbon source and reduce fitness. Finally, we demonstrate that FrmB is important for the formation of small colony variants (SCVs), a clinically relevant metabolic transition that is associated with chronic infection and antibiotic resistance.

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License: CC-BY-ND-4.0