Effect of emodin on Streptococcus suis by targeting β-ketoacyl-acyl carrier protein synthase Ⅱ

Abstract

Background

Streptococcus suis is a zoonotic pathogen that causes meningitis, septicaemia, endocarditis, arthritis, and pneumonia in human beings. With the increasing prevalence of S. suis infections and a general decline in the effectiveness of antibiotics, the development of novel drugs that have effect on S. suis is extremely urgent. Emodin, a natural anthraquinone derivative of Rheum palmatum L., Reynoutria japonica Houtt., Polygonum multiflorum Thunb. and Cassia obtusifolia L., has been reported to exert anti-S. suis effect; however, the specific mechanism of the anti-S. suis action by targeting β-ketoacyl-acyl carrier protein synthase Ⅱ (FabF) in the fatty acid synthesis pathway remains unexplored.

Purpose

We sought to reveal the potential role of emodin to prevent S. suis infection, investigate its mechanism of anti-S. suis action, and provide further evidence of emodin as an alternative to traditional antibiotic agents.

Methods

The in vitro anti-S. suis properties of emodin were assessed through minimum inhibitory concentration (MIC) assays, and time-kill assays. Subsequently, the mechanisms underlying emodin’s mode of action at the molecular level by targeting FabF were elucidated using molecular docking, site-directed mutagenesis, bio-layer interferometry assays, and cellular thermal shift assays. Finally, metabolomics, cell membrane phospholipid content assay and biochemical parameters assays were used to detect emodin disrupting cell membrane integrity and function by affecting fatty acid biosynthesis.

Results

In this study, we have identified that emodin inhibits S. suis by suppressing free fatty acids (FFAs) synthesis and disrupting phospholipid production by targeting FabF, a key enzyme in the fatty acid biosynthesis pathway. This interference compromises the integrity and functionality of the cell membranes of S. suis. Emodin also triggers the dissipation of the proton motive force, accelerates the tricarboxylic acid cycle, and enhances cellular respiration, ultimately leading to S. suis cell death.

Conclusion

This study suggested that emodin inhibits the growth of S. suis via targeting FabF and the inhibition of fatty acid biosynthesis through enzyme-targeted drug design. This represents a novel strategy for developing antimicrobial agents against S. suis and addressing the challenge of antibiotic resistance.