Streptococcus suis (S. suis) is a significant zoonotic pathogen that substantially threatens to both swine and humans, particularly in intensive farming and global food security. It has a high zoonotic potential when undercooked pork products are consumed or when there is close contact with contaminated raw pork products or infected pigs [1,2]. This Gram-positive bacterium is responsible for severe infections, including meningitis, septicaemia, and endocarditis [3]. The emergence of antibiotic resistance in S. suis is a growing concern, especially its tolerance to aminoglycosides, which are commonly used antibiotics in both veterinary and human medicine [4,5].

Bacterial metabolism plays a crucial role in developing antibiotic resistance and tolerance, particularly in the formation of persisters and biofilms, which are inherently resistance to many antibiotics [6,7]. The metabolic state of a bacterial cell influences its susceptibility to antibiotics; for instance, cells in a dormant state often survive antibiotic treatment because of their reduced metabolic activity [8,9]. Aminoglycosides exert their bactericidal effects by binding to the bacterial ribosome and disrupting protein synthesis [10]. However, their uptake and efficacy are closely linked to the proton motive force (PMF) generated during aerobic respiration [11]. The bacteria shift towards lactic acid fermentation rather than utilizing the tricarboxylic acid (TCA) cycle for aerobic respiration. This metabolic shift leads to a decreased PMF, limiting the uptake of aminoglycosides and reducing their effectiveness [[12], [13], [14]].

Given the limitations of current antibiotic therapies and the urgent need for novel approaches to combat resistant S. suis, our research focuses on targeting the metabolic pathways that contribute to antibiotic resistance in S. suis. Specifically, we aim to disrupt the bacterium’s reliance on lactic acid fermentation by inhibiting lactate dehydrogenase (LDH), the key enzyme responsible for converting pyruvate to lactate under anaerobic conditions [15,16]. By inhibiting LDH, we hypothesize that S. suis will be forced to engage in aerobic respiration, thereby increasing the PMF and enhancing the bactericidal action of aminoglycosides. In this study, we employed a virtual screening approach to identify potential LDH inhibitors from a library of small molecules derived from traditional Chinese medicine (TCM). TCM offers a rich reservoir of bioactive compounds with unique properties. Many TCM-derived compounds have demonstrated low toxicity, environmental sustainability, and specificity in targeting biological pathways [17]. The integration of TCM with modern drug discovery technologies, such as virtual screening, not only enhances the efficiency of the screening process but also aligns with the global trend towards green and sustainable pharmacology [18,19].

By shifting the metabolic balance from fermentation to respiration, we aim to enhance the efficacy of aminoglycosides. This approach could provide a dual benefit: increasing antibiotic therapy’s immediate effectiveness while also reducing the likelihood of resistance development. Identifying and optimizing LDH inhibitors from TCM through virtual screening marks a promising step towards developing novel therapeutic strategies against S. suis. These small molecules offer the potential to be developed as adjuvants to existing antibiotic therapies, particularly aminoglycosides, thereby extending their usefulness in the face of rising resistance.