Catalytic activity of the prepilin peptidase PilD is required for full P. aeruginosa virulence in a nematode infection model
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Pseudomonas aeruginosa is an ESKAPE pathogen of concern because of its antibiotic resistance and ability to colonize and infect humans in myriad diverse clinical settings, from the lungs of cystic fibrosis patients to burn wounds. Antivirulence strategies have emerged as an alternative to antibiotics for treating P. aeruginosa and other pathogens. One proposed antivirulence target is the prepilin peptidase PilD because of its centrality in two virulence mechanisms: the Type IV pili and the Type II Secretion System (T2SS). Substitution of invariant aspartic acids in the putative active site of PilD led to loss of peptidase activity in an in vitro cleavage assay and abrogation of both pilus-dependent twitching motility and T2SS-dependent protease secretion. Subsequently, this study utilized a simple Caenorhabditis elegans animal infection model to investigate the in vivo magnitude of the role of PilD on P. aeruginosa virulence. In the absence of functional PilD—either through gene disruption or catalytic inactivation— P. aeruginosa exhibited delayed lethality and was reliant on other virulence mechanisms to infect and kill C. elegans. These findings highlight PilD as a valuable antivirulence target in P. aeruginosa .
Author summary
Pseudomonas aeruginosa is a tough-to-treat bacterial pathogen that causes serious infections in hospital settings, especially for people with burns, lung disease, or weakened immune systems. As antibiotic resistance grows, researchers seek new ways to stop infections— not by killing bacteria directly, but by blocking the mechanisms they use to cause disease. If a drug could interfere with multiple virulence pathways at the same time, that would make it particularly effective at stopping infection. One possible new drug target to shut down multiple virulence factors is the enzyme PilD, which helps P. aeruginosa build two different systems it uses to stick to tissues and secrete harmful proteins. In this study, we tested what happens when PilD is removed or disabled. Using the small, transparent worm Caenorhabditis elegans as a simple model for animal infection, we found that without active PilD, P. aeruginosa bacteria were much slower to kill their host. Even though the bacteria could still grow, they struggled to attach, spread, and cause damage. These results highlight PilD as a promising target for antivirulence treatments—new types of drugs that disarm harmful bacteria without driving antibiotic resistance. Our findings also support the use of C. elegans as a fast, cost-effective system to test potential treatments in living hosts.
