Targeting type III secretion in Yersinia pestis.

Area of Science:

• Microbiology
• Bacteriology
• Pathogen Virulence Mechanisms

Background:

• Yersinia pestis causes plague and uses a type III secretion system (T3SS) to inject Yersinia outer proteins (Yops) into host cells.
• The T3SS is essential for Y. pestis virulence, making it a critical target for developing novel anti-plague therapeutics.

Purpose of the Study:

• To identify small molecules that inhibit the Y. pestis T3SS using a high-throughput screening approach.
• To evaluate the efficacy and specificity of identified inhibitors against Yop secretion and bacterial cytotoxicity.

Main Methods:

• A high-throughput screen of 70,966 chemical compounds was performed to identify inhibitors of Y. pestis T3SS.
• Presumptive inhibitors underwent secondary assays to confirm Yop secretion inhibition, assess cytotoxicity, and evaluate effects on bacterial growth.

Main Results:

• 421 presumptive inhibitors were identified, with eight selected for further analysis.
• Four compounds demonstrated effective inhibition of Yop secretion at micromolar concentrations.
• Three of these compounds protected HeLa cells from T3SS-dependent cytotoxicity, and none inhibited bacterial growth at tested concentrations.

Conclusions:

• Four novel chemical scaffolds were identified as promising leads for Y. pestis T3SS inhibitor development.
• These compounds represent a distinct chemical class compared to previously described inhibitors.
• Further structure-activity relationship studies are warranted to develop potential anti-plague therapeutics.