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

Abstract

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.

Characterization of Small‐Molecule Scaffolds That Bind to the Shigella Type III Secretion System Protein IpaD

“…There is a growing number of small molecules that have been reported to inhibit the T3SS, however, the specific targets within the T3SS for many of those inhibitors remain unknown. [9, 18] Likewise, the number of known small molecules that bind directly to T3SS proteins are limited. [9] Currently, the only known small molecules that interact with IpaD, a protein that plays a critical role in the T3SS and pathogenesis of Shigella , are the bile salt sterols deoxycholate, [11a, 11b, 19] cholate, chenodeoxycholate, and taurodeoxycholate.…”

“…[7b, 7d, 8] Because the T3SS is essential for virulence, it is an attractive target for developing anti-infectives or drugs that prevent infection but not necessarily destroy pathogens. [9] IpaD in particular is an attractive target for several reasons: (i) it is essential for infectivity; [10] (ii) it is exposed on the bacterial surface; and (iii) it is conserved in other bacteria. Developing new anti-infectives that target IpaD require the identification of small molecules that can bind and inhibit the function of IpaD.…”

In silico Determination of Efficiency of Plant Secondary Metabolites to Eradicate Trachoma- A Blinding Keratoconjuctivitis Disease

“…The protein targeted in the present study is CdsD, which has 829 aminoacids and has a transmembrane domain (530-551 residues), a C-terminal periplasmic part and Nterminal cytosolic part. Since, this CdsD takes part in the formation of outer ring structure of the IM-ring injectisome, this protein is considered significant to target in order to interrupt the pathogenic development of the organism, C. trachomatis (McShan and Guzman, 2015). Moreover, CdsD has a unique N-terminus containing FHA domain which undergoes phosphorylation and capable to interact with the novel subset of inner membrane proteins (Betts-Hampikian and Fields, 2010).…”

Using Integrated Bioinformatics Strategy to Identify Critical Factors for the Structural Integrity of Salmonella T3SS

“…For these reasons, T3SS has become a very important target for drug development [37] . Several small molecules have been reported to disrupt the assembly and function of T3SS in various model systems [42][43][44] . To facilitate mechanistic studies on the structural integrity of T3SS and to facilitate the discovery of new drugs that target T3SS structural proteins, thorough understanding on the three-dimensional structures and on the interaction partners of T3SS structural proteins becomes a prerequisite.…”