Molecular Targets and Strategies for Inhibition of the Bacterial Type III Secretion System (T3SS); Inhibitors Directly Binding to T3SS Components

Abstract

The type III secretion system (T3SS) is a virulence apparatus used by many Gram-negative pathogenic bacteria to cause infections. Pathogens utilizing a T3SS are responsible for millions of infections yearly. Since many T3SS knockout strains are incapable of causing systemic infection, the T3SS has emerged as an attractive anti-virulence target for therapeutic design. The T3SS is a multiprotein molecular syringe that enables pathogens to inject effector proteins into host cells. These effectors modify host cell mechanisms in a variety of ways beneficial to the pathogen. Due to the T3SS’s complex nature, there are numerous ways in which it can be targeted. This review will be focused on the direct targeting of components of the T3SS, including the needle, translocon, basal body, sorting platform, and effector proteins. Inhibitors will be considered a direct inhibitor if they have a binding partner that is a T3SS component, regardless of the inhibitory effect being structural or functional.

Peptidomimetics as Potential Anti-Virulence Drugs Against Resistant Bacterial Pathogens

“…T3SS is a secretion system associated with flagellum components (Flagellar-T3SS) transport in motile bacteria, but also with virulence effectors transport in pathogenic Gram-negative bacteria through the Non-Flagellar-T3SS system (NF-T3SS) ( Hajra et al, 2021 ). NF-T3SS is a multiprotein complex that transports bacterial virulence effectors directly from the pathogen cytosol into the host cell through a needle-like structure that traverses pathogen and host cell membranes ( Hajra et al, 2021 ; Hotinger et al, 2021b ). Structurally, NF-T3SS is composed of five major elements that include the cytoplasmic complex, export apparatus, basal body, needle, and translocon ( Hajra et al, 2021 ; Hotinger et al, 2021b ).…”

The Case against Antibiotics and for Anti-Virulence Therapeutics

“…Although no T3SS inhibitors have been FDA approved, the T3SS is one of the most validated anti-virulence targets, with many compounds in development (Table 1) [225]. Small molecule inhibitors of the T3SS have been shown to increase survival rates after infection with otherwise lethal doses of the bacterial pathogen (Table 1) [14,232] McHugh et al showed the ability of the natural product aurodox to decrease effector protein secretion and decrease the infectious potential of enterohemorrhagic E. coli (EHEC). Transcriptomal analysis of genes affected by aurodox showed downregulation of 25 of the 41 genes related to the T3SS, including ler, a major activator of the T3SS [228].…”

Secretory System Components as Potential Prophylactic Targets for Bacterial Pathogens

“…Overall architecture and function of the type III secretion system in the pathogen have been described in detail [23,197,198] and type II has been detailed in P. aeruginosa as well [199][200][201][202][203]. In an animal model of infection, the type III system is the most important one for virulence with type II providing a minor role [204].…”

“…The infection process requires not only finding a receptor on the human host but also the ability to secrete protein components in a coordinated process to overcome the immune defenses of the host and establish a suitable niche to replicate after infection. Theoretically, blocking the bacterial transport by virulence systems would block the infection and render the bacterial pathogens defenseless [23][24][25]. Since the bacterial transport systems are required for bacterial pathogens to start and continue an infection process and can be easily identified bioinformatically from the DNA sequences [26], there is an alternative vaccine design strategy that could be used to prevent bacterial infections.…”