Pentamidine inhibition of streptopain attenuates Streptococcus pyogenes virulence

Area of Science:

• Microbiology
• Infectious Diseases
• Drug Discovery

Background:

• Group A Streptococcus (GAS) causes significant morbidity and mortality, especially in resource-poor areas.
• Conventional antibiotic monotherapy often fails, necessitating new therapeutic approaches.
• Streptopain (SpeB), a GAS protease, is crucial for pathogenesis, inflammation, and immune evasion.

Purpose of the Study:

• To identify novel compounds that inhibit streptopain activity.
• To evaluate lead compounds for adjunctive therapeutic benefits against GAS.
• To explore drug repurposing for GAS infections.

Main Methods:

• Screened 400 diverse off-patent compounds for streptopain protease inhibitors.
• Tested lead compounds for activity at lower concentrations and anti-virulence effects in vitro.
• Assessed the impact of streptopain inhibition on GAS susceptibility to human immune cells.

Main Results:

• Pentamidine, an existing anti-protozoal drug, significantly inhibited streptopain.
• Streptopain inhibition by pentamidine restored GAS susceptibility to innate immune cell killing.
• Identified pentamidine as a promising lead compound for GAS adjunctive therapy.

Conclusions:

• Pentamidine demonstrates potential as a repurposed drug for treating GAS infections.
• Inhibiting streptopain is a viable strategy to enhance host defense against GAS.
• This study highlights unexploited molecules for novel drug discovery against GAS.