The Bacterial Type III Secretion System as a Target for Developing New Antibiotics

Antibiotic resistance in pathogens requires new targets for developing novel antibacterials. The bacterial type III secretion system (T3SS) is an attractive target for developing antibacterials as it is essential in the pathogenesis of many Gram‐negative bacteria. The T3SS consists of structural proteins, effectors, and chaperones. Over 20 different structural proteins assemble into a complex nanoinjector that punctures a hole on the eukaryotic cell membrane to allow the delivery of effectors directly into the host cell cytoplasm. Defects in the assembly and function of the T3SS render bacteria non‐infective. Two major classes of small molecules, salicylidene acylhydrazides and thiazolidinones, have been shown to inhibit multiple genera of bacteria through the T3SS. Many additional chemically and structurally diverse classes of small molecule inhibitors of the T3SS have been identified as well. While specific targets within the T3SS of a few inhibitors have been suggested, the vast majority of specific protein targets within the T3SS remain to be identified or characterized. Other T3SS inhibitors include polymers, proteins, and polypeptides mimics. In addition, T3SS activity is regulated by its interaction with biologically relevant molecules, such as bile salts and sterols, which could serve as scaffolds for drug design. The type III secretion system is essential in the virulence of many Gram‐negative bacterial pathogens that cause serious infectious diseases in humans and offers an excellent target for developing novel antibiotics. This review summarizes the currently known inhibitors of the type III secretion system. These inhibitors are small molecules, peptides, proteins, and polymers that could potentially be used as starting points for developing antibacterials.