PurA is the main target of aurodox, a type III secretion system inhibitor

Area of Science:

• Microbiology
• Drug Discovery
• Molecular Biology

Background:

• Antimicrobial resistance (AMR) poses a significant global health threat, challenging traditional antibiotic approaches.
• The type III secretion system (T3SS) is crucial for bacterial pathogenesis but not essential for survival, making it an attractive target for novel anti-infectives.
• T3SS inhibitors can reduce evolutionary pressure for resistance development.

Purpose of the Study:

• To identify the molecular target of aurodox (AD), a previously identified type III secretion system (T3SS) inhibitor.
• To elucidate the mechanism by which AD affects bacterial virulence.
• To explore the potential of the identified target for developing new anti-infective strategies.

Main Methods:

• Utilized a combination of chemistry and genetic biology approaches.
• Screened for specific T3SS inhibitors.
• Investigated the binding of aurodox (AD) to bacterial proteins.
• Assessed the impact of AD on T3SS-mediated virulence in vitro and in vivo.

Main Results:

• Identified adenylosuccinate synthase (PurA) as the molecular target of aurodox (AD).
• Demonstrated that AD binding to PurA suppresses T3SS secreted protein production.
• Showed that this suppression results in reduced bacterial virulence in experimental models.
• Confirmed AD's efficacy in both in vitro and in vivo settings.

Conclusions:

• Adenylosuccinate synthase (PurA) is a viable target for novel anti-infective drug development.
• Targeting PurA offers a promising strategy to combat bacterial infections and overcome antimicrobial resistance.
• This research opens avenues for PurA-based anti-infective therapies and vaccinations targeting T3SS regulation.