Novel 1-hydroxy phenothiazinium-based derivative protects against bacterial sepsis by inhibiting AAK1-mediated LPS...

Area of Science:

• Immunology
• Pharmacology
• Molecular Biology

Background:

• Sepsis is a critical global health issue with high mortality, often stemming from severe infections and host response dysregulation.
• Current therapeutic options for sepsis are limited due to an incomplete understanding of its underlying mechanisms.
• Previous research indicated the potential of blocking the caspase-11 pathway in mitigating sepsis-induced complications.

Purpose of the Study:

• To identify novel therapeutic agents for sepsis by screening chemical libraries.
• To investigate the mechanism of action of identified compounds in dampening sepsis-related inflammation.
• To evaluate the in vivo efficacy of promising drug candidates in preclinical sepsis models.

Main Methods:

• Screening of a chemical pool using bacterial outer membrane vesicle (OMV)-challenged macrophages.
• In vitro studies to elucidate the molecular targets and pathways affected by the identified compound.
• In vivo studies using gene-modified mouse models of sepsis to assess therapeutic effects.

Main Results:

• A novel phenothiazinium derivative, PHZ-OH, was identified as a potent inhibitor of caspase-11-dependent pyroptosis.
• PHZ-OH targets AP2-associated protein kinase 1 (AAK1), preventing LPS internalization and subsequent caspase-11 activation.
• Administration of PHZ-OH significantly protected mice against sepsis-induced coagulation, multiple organ dysfunction, and mortality.

Conclusions:

• Targeting AAK1-mediated LPS internalization presents a promising therapeutic strategy for sepsis.
• PHZ-OH demonstrates significant potential as a therapeutic agent and a scaffold for developing new sepsis treatments.
• The findings highlight the critical role of AAK1 in caspase-11 signaling during sepsis.