Targeting the Type Three Secretion System in Pseudomonas aeruginosa

The injectisome type three secretion system (T3SS) is a major virulence factor in Pseudomonas aeruginosa. This bacterium is responsible for severe infections in immunosuppressed or cystic fibrosis patients and has become resistant to many antibiotics. Inhibitors of T3SS may therefore constitute an innovative therapeutic target. After a brief description of the T3SS and its regulation, this review presents strategies to inhibit T3SS-mediated toxicity and describes the main families of existing inhibitors. Over the past few years, 12 classes of small-molecule inhibitors and two types of antibody have been discovered and evaluated in vitro for their capacity to inhibit T3SS expression or function, and to protect host cells from T3SS-mediated cytotoxicity. While only one small molecule has been tested in vivo, a bifunctional antibody targeting both the translocation apparatus of the T3SS and a surface polysaccharide is currently in Phase II clinical trials.

TrendsDisarming bacteria by reducing their virulence is a promising therapeutic strategy in a world of increasing antibiotic resistance. The injectisome T3SS of P. aeruginosa causes direct cytotoxicity and also activates NLRC4 inflammasome cascade in the host.A series of small-molecules inhibitors have been identified acting on gene transcription, ATPase or basal body export activity, effector secretion or translocation, and blocking effector enzymatic activity. Most of them have proved effective in vitro, but in vivo demonstration of their efficacy remains scarce.Antibodies targeting the translocon and bispecific antibodies targeting both the translocon and a surface polysaccharide have reached Phase II trials, but the first antibodies were abandoned for insufficient efficacy.Immunomodulation can counteract cytokine imbalance related to inflammasome activation.