Gallic Acid Restores the Sulfonamide Sensitivity of Multidrug-Resistant Streptococcus suis via Polypharmaceology Mechanism

Due to the large amount of antibiotics used for human therapy, agriculture, and even aquaculture, the emergence of multidrug-resistant Streptococcus suis (S. suis) led to serious public health threats. Antibiotic-assisted strategies have emerged as a promising approach to alleviate this crisis. Here, the polyphenolic compound gallic acid was found to enhance sulfonamides against multidrug-resistant S. suis. Mechanistic analysis revealed that gallic acid effectively disrupts the integrity and function of the cytoplasmic membrane by dissipating the proton motive force of bacteria. Moreover, we found that gallic acid regulates the expression of dihydrofolate reductase, which in turn inhibits tetrahydrofolate synthesis. As a result of polypharmacology, gallic acid can fully restore sulfadiazine sodium activity in the animal infection model without any drug resistances. Our findings provide an insightful view into the threats of antibiotic resistance. It could become a promising strategy to resolve this crisis.

Automated summary

Owing to the excessive use of antibiotics in various sectors, multidrug-resistant Streptococcus suis (S. suis) has become a serious public health concern. Polyphenolic compound gallic acid has shown potential in improving the efficacy of sulfonamide antibiotics against multidrug-resistant S. suis. Mechanistic analysis revealed that gallic acid disrupts the integrity and function of the bacteria's cytoplasmic membrane by depleting the proton motive force. Additionally, gallic acid was found to regulate the expression of dihydrofolate reductase, inhibiting tetrahydrofolate synthesis. In an animal infection model, gallic acid successfully restored the activity of sulfadiazine sodium without inducing drug resistance. These findings offer valuable insights into the threat of antibiotic resistance and propose a promising strategy to overcome this crisis.