Pseudomonas aeruginosa, an opportunistic human pathogen, expresses protease IV (PIV) for infection. Since the PIV activity can be inhibited by its propeptide, we tried to alleviate the severity of P. aeruginosa infection using the purified PIV propeptide (PIV_pp). The PIV_pp treatment of P. aeruginosa could significantly inhibit the PIV activity and reduce the virulence of P. aeruginosa in multiple invertebrate infection models, such as nematodes, brine shrimp, and mealworms. The effectiveness of PIV_pp was further confirmed using mouse skin infection and acute/chronic lung infection models. The amount of PIV_pp that inhibited the PIV activity of P. aeruginosa by 65% could alleviate the severity of infection significantly in all of the skin and acute/chronic lung infections. In addition, the PIV_pp treatment of P. aeruginosa facilitated the healing of the skin wound infections and repressed the growth of P. aeruginosa in the infected lung. The PIV_pp itself did not cause the induction of inflammatory cytokines or have any harmful effects on host tissues and did not affect bacterial growth. Taken together, P. aeruginosa infections can be alleviated by PIV_pp treatment. IMPORTANCE 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.

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