Pyruvate availability governs adaptive antibiotic resistance in Staphylococcus aureus

ABSTRACT: Adaptive resistance enables bacteria to survive antibiotic stress before stable resistance emerges, yet the metabolic requirements that permit this transitional state remain unclear. Using vancomycin-intermediate Staphylococcus aureus (VISA) evolution as a model, we identify pyruvate availability as metabolic checkpoint for adaptive antibiotic resistance. Adaptive laboratory evolution shows that SceD, but not the related lytic transglycosylase IsaA, is strongly induced and supports efficient progression toward the VISA phenotype. Genomic, transcriptomic, and [U-¹³C] glucose-tracing analyses show that sceD deletion redirects adaptive evolutionary trajectories and exposes a bottleneck at the phosphoenolpyruvate-to-pyruvate node while leaving upstream glycolysis largely intact. This bottleneck limits pyruvate-derived anaplerosis, nucleotide metabolism, UDP-GlcNAc biosynthesis, and energy balance. Rescue experiments show that pyruvate and pyruvate-derived anaplerotic intermediates, rather than upstream carbon sources, peptidoglycan turnover products or nucleobases, restore adaptive capacity. Genetic disruption of pyk nearly abolishes adaptive evolution, while exogenous pyruvate restores or enhances adaptation. SceD interacts with pyruvate kinase (Pyk) and modulates Pyk enzymatic activity, providing one route by which envelope stress is coupled to pyruvate metabolism. Pyruvate dependence extends across antibiotic classes, establishing pyruvate availability as a convergent metabolic requirement for adaptive resistance.

INSTRUMENT(S): Liquid Chromatography MS - alternating - hilic

PROVIDER: MTBLS16117 | MetaboLights | 2026-10-22

REPOSITORIES: MetaboLights