Inhibition of bacterial type three secretion system mediated cell death by small chemical inhibitors

Abstract

Current antibiotic therapies for bacterial pathogens target common components essential for viability of all bacteria. This strategy has been very effective in combating bacterial infections but fails to discriminate against non-pathogens and places tremendous pressure on organisms to evolve antibiotic resistance mechanisms. A promising alternative to targeting bacterial viability is to inhibit virulence mechanisms that are unique to pathogenic bacteria and modulate interaction with the host. Gram-negative bacteria utilize a type three secretion system (T3SS) to inject effector molecules from the bacterial cytoplasm directly into the host, where the effectors subvert and modify host cell function for colonization and immune evasion. Using a high-throughput cell based screen we identified three inhibitors of the Gram negative T3SS; quinolozone compound PA T3SS-9 blocks P. aeruginosa ExoU mediated cell death by targeting downstream of ExoU phospholipase A2 activity, and phenylquinazolinamine compound PA T3SS-11 and 2-phenylbenzoxazole compound PA T3SS-19 are broad range inhibitors of T3SS mediated cell death.