Small-Molecule Inhibitors of the Type III Secretion System

Abstract

Drug-resistant pathogens have presented increasing challenges to the discovery and development of new antibacterial agents. The type III secretion system (T3SS), existing in bacterial chromosomes or plasmids, is one of the most complicated protein secretion systems. T3SSs of animal and plant pathogens possess many highly conserved main structural components comprised of about 20 proteins. Many Gram-negative bacteria carry T3SS as a major virulence determinant, and using the T3SS, the bacteria secrete and inject effector proteins into target host cells, triggering disease symptoms. Therefore, T3SS has emerged as an attractive target for antimicrobial therapeutics. In recent years, many T3SS-targeting small-molecule inhibitors have been discovered; these inhibitors prevent the bacteria from injecting effector proteins and from causing pathophysiology in host cells. Targeting the virulence of Gram-negative pathogens, rather than their survival, is an innovative and promising approach that may greatly reduce selection pressures on pathogens to develop drug-resistant mutations. This article summarizes recent progress in the search for promising small-molecule T3SS inhibitors that target the secretion and translocation of bacterial effector proteins.

Keywords: Gram-negative bacteria; antibacterial agents; effector proteins; pathogens; small-molecule inhibitors; type III secretion system; virulence.

Figure 1

Schematic diagram of the T3SS in which the needle apparatus is contacting the host cell. OM, outer membrane; IM, inner membrane.

Figure 2

Schematic diagram of anti-virulence strategies by using T3SS inhibitors in Gram-negative bacterial pathogens.

Figure 3

Structures of INP0007 (1), INP0010 (2) and INP0400 (3).

Figure 4

Structure of N-hydroxybenzimidazoles.

Figure 5

Structures of 9–13.

Figure 6

Structures of Compounds 14a–14d.

Figure 7

Alteration of the production of T3SS effectors ExoS and ExoT by T3SS inhibitors. P. aeruginosa PAO1 cells were grown in LB broth supplemented with 10 mM NTA (nitrilotriacetic acid) and 250 μM inhibitors. The same volume of DMSO was added to the culture as a negative control. The Western blot was performed using an anti-ExoS antibody.

Figure 8

Structures of Compounds 15–18.

Figure 9

Structures of Compounds 19–25.

Figure 10

Structures of caminoside A, guadinomine B and aurodox.