Alleviation of Pseudomonas aeruginosa Infection by Propeptide-Mediated Inhibition of Protease IV

Abstract

Pseudomonas aeruginosa is a highly antibiotic-resistant pathogen and is extremely difficult to treat. Instead of using conventional antibiotics, we attempted to alleviate P. aeruginosa infection using factors that P. aeruginosa itself produces naturally. Extracellular proteases are powerful virulence factors and important targets to control the P. aeruginosa infections. Propeptides are originally expressed as part of extracellular proteases, inhibiting their activity until they go out of the cell, preventing them from becoming toxic to the cells themselves. We confirmed, from multiple animal experiments, that treating P. aeruginosa with the purified propeptide can alleviate its infectivity. Propeptides specifically inhibit only their cognate protease without inhibiting other essential proteases of the host. The development of resistance can be avoided because the propeptide-mediated inhibition is an inherent mechanism of P. aeruginosa; hence, it will be difficult for P. aeruginosa to alter this mechanism. Since propeptides do not affect bacterial growth, there is no selective pressure to develop resistant cells.