Research Progress on Small Molecular Inhibitors of the Type 3 Secretion System

Abstract

The overuse of antibiotics has led to severe bacterial drug resistance. Blocking pathogen virulence devices is a highly effective approach to combating bacterial resistance worldwide. Type three secretion systems (T3SSs) are significant virulence factors in Gram-negative pathogens. Inhibition of these systems can effectively weaken infection whilst having no significant effect on bacterial growth. Therefore, T3SS inhibitors may be a powerful weapon against resistance in Gram-negative bacteria, and there has been increasing interest in the research and development of T3SS inhibitors. This review outlines several reported small-molecule inhibitors of the T3SS, covering those of synthetic and natural origin, including their sources, structures, and mechanisms of action.

Antibiotics in the clinical pipeline as of December 2022

“…Non-traditional antibacterial compounds in phase-II trials (Table 4, Fig. 7) Fluorothiazinon (40) (ftortiazinon, fluorothyazinon, C-55; po) is an orally administered inhibitor of the bacterial type III secretion system (T3SS), which is a highly conserved G-ve anti-virulence target [226] Fluorothiazinon (40) was developed by the Gamaleya Research Institute of Epidemiology and Microbiology (Moscow, Russia) [227][228][229][230], and has been evaluated in a phase-II trial (NCT03638830) in combination with the cephalosporin cefepime (41) as a potential treatment for patients with cUTI caused by P. aeruginosa.…”

A Review of Antibacterial Candidates with New Modes of Action

“…Type III secretion systems (T3SS) are multiprotein complexes that translocate effector proteins directly from the bacterial cytosol into a host cell via a needle-like mechanism that spans the G−ve cell envelope. 365 The T3SS plays a central role in the virulence of many G−ve human pathogens. Fluorothiazinon (99) (ftortiazinon, fluorothyazinon, C-55) is a T3SS inhibitor that has been shown to have in vivo antivirulence activity (reduced bacterial loads and inflammation) against Chlamydia trachomatis, 366,367 Salmonella, 368,369 P. aeruginosa, 370 A. baumannii, 371 and uropathogenic E. coli (UPEC).…”

“…Type III secretion systems (T3SS) are multiprotein complexes that translocate effector proteins directly from the bacterial cytosol into a host cell via a needle-like mechanism that spans the G–ve cell envelope . The T3SS plays a central role in the virulence of many G–ve human pathogens.…”