Disrupting bacterial metabolism by targeting LDH reverses aminoglycoside resistance in Streptococcus suis

The emergence of drug-resistant Streptococcus suis (S. suis), driven primarily by antibiotic overuse in veterinary medicine and agriculture practices, threatens global public health. Antibiotic adjuvants that potentiate existing drugs offer a promising strategy to combat resistance.

We screened two small molecules targeting lactic dehydrogenase of S. suis. Hit compounds panaxadiol (PD) and vitamin D₂ (VD₂) were evaluated for metabolic modulation via aerobic respiration assays, NADH quantification, proton motive force (PMF) measurements, and metabonomics analysis. Aminoglycoside uptake and bactericidal activity were assessed in vitro and in vivo. All data are presented as mean ± SD from three independent experiments, and significance was determined by unpaired t tests (*P < 0.05, **P < 0.01, ***P < 0.001).

PD and VD₂ inhibited S. suis lactic dehydrogenase, suppressing anaerobic metabolism and redirecting pyruvate to the tricarboxylic acid cycle. This shift increased NADH production, amplified PMF, and enhanced uptake of PMF-dependent aminoglycosides. Both compounds synergized with aminoglycosides, significantly improving bactericidal efficacy against S. suis in vitro and in animal models.

Targeting S. suis metabolic pathways with PD or VD₂ restores aminoglycoside susceptibility, offering an adjuvant strategy to counter antibiotic resistance.