The erythromycin polyketide compound TMC-154 stimulates ROS generation to exert antibacterial effects against...

Area of Science:

• Microbiology
• Biochemistry
• Pharmacology

Background:

• Streptococcus pyogenes is a significant human pathogen causing diverse infections.
• Antibiotic resistance necessitates the search for novel antibacterial agents.
• The antibacterial mechanism of TMC-154, a metabolite from Clonostachys rogersoniana, remained unelucidated.

Purpose of the Study:

• To investigate the antibacterial mechanism of TMC-154 against Streptococcus pyogenes.
• To identify signaling pathways affected by TMC-154 using bioinformatics.
• To validate the role of reactive oxygen species (ROS) in TMC-154's antibacterial activity.

Main Methods:

• Proteomics and bioinformatics (KEGG pathway analysis) were employed to explore TMC-154's mechanism.
• Cell biology experiments assessed ROS generation in Streptococcus pyogenes upon TMC-154 treatment.
• Antioxidant N-acetyl L-cysteine was used to inhibit ROS and evaluate its effect on TMC-154's antibacterial activity.
• Synergistic effects of TMC-154 with existing antibiotics (ciprofloxacin, chloramphenicol) were tested.

Main Results:

• KEGG pathway analysis revealed eight associated pathways, including oxidative phosphorylation and cationic antimicrobial peptide (CAMP) resistance.
• TMC-154 was confirmed to induce ROS generation in Streptococcus pyogenes.
• Inhibition of ROS generation by N-acetyl L-cysteine blocked the antibacterial effects of TMC-154.
• TMC-154 demonstrated synergistic antibacterial effects when combined with ciprofloxacin or chloramphenicol.

Conclusions:

• TMC-154 exerts antibacterial effects against Streptococcus pyogenes primarily through the induction of ROS.
• The compound shows potential as a novel therapeutic agent for S. pyogenes infections, especially in the context of rising antibiotic resistance.
• TMC-154 may offer a new strategy for combating infections caused by this important human pathogen.