Table 1:
Possible Targets and Function of Small Molecule Inhibitors of the T3SS
| Compound | Organism | Target | Inhibits bacterial growth? | Toxic to cells? | In vivo studies? | Phenotype/Readout | Refs. |
|---|---|---|---|---|---|---|---|
| SAH (C1, C2) SABC4 |
Yersinia pseudotuberculosis | No | NT | No | Inhibits T3SS transcription and Yop secretion; C2 and C4 inhibit flagellar motility | (13) | |
| SAH (C1–C23) C1-INP0007 |
Y. pseudotuberculosis | No | No | No | Inhibits secretion and translocation | (14) | |
| SAH C1-INP0007 SAH C11-INP0403 |
Salmonella enterica | No | No | Yes | Inhibits secretion and blocks invasion; First study to validate SAH in vivo using bovine intestinal ligated loops | (27) | |
| SAH C11-INP0403 (ME0053) |
S. enterica | Suggested indirect effect-iron chelation | No | No | No | Inhibits T3SS transcription and secretion; Upregulation of iron acquisition | (25) |
| SAH INP0341 SAH INP0400 |
Chlamydia trachomatis | Suggested indirect effect-iron chelation | No | No | Yes | Inhibits T3SS transcription; Upregulation of iron acquisition; Protects mice against vaginal infection when administered topically | (35, 80, 81) |
| SAH INP0341 | C. trachomatis | No | No | No | Mutations isolated in HemG suggesting indirect effect on T3SS | (37) | |
| SAH INP0400 SAHINP0402 (C15) | Shigella flexneri | Suggested to inhibit T3SS basal needle assembly | No | No | No | Inhibits secretion and blocks invasion; Fewer and shorter needle assembly | (17) |
| SAHME0052(C8, INP0010) SAHMEOO53(C11, INP0403) SAHME0054(C10, INP0401) SAH ME0055(C17; INPOO31) |
EHEC | Suggested to inhibit T3SS regulators | No | No | No | Inhibits secretion | (15) |
| SAH ME0052(C8, INPOO10) SAH ME0055(C17, INPOO31) |
Y. pseudotuberculosis Escherichia coli | No | No | No | Inhibits secretion; Pull down assays identified WrbA, FoIX and Tpx bind to SAH suggesting indirect effect on T3SS | (36) | |
| SAH INP0404 SAH INP0405 |
S. enterica | No | No | NA | Mutations isolated in FlhAgene suggest targeting of T3SS basal body | (19) | |
| SAH INP0341 | Pseudomonas aeruginosa | No | No | No | Inhibits T3SS transcription and ExoS secretion | (39) | |
| SAH RCZ12 and RCZ20 |
EHEC | EspD ‒ needle pore protein | No | No | No | Inhibits EspD secretion; Fewer/shorter needle assembly | (38) |
| SAB Compound 4 | Y. pseudotuberculosis | No | No | No | Inhibits secretion | (40) | |
| SAH INP0007 | Y. pseudotuberculosis | No | No | No | Affects YscD puncta formation | (40) | |
| SAH INP0010 | Y. pseudotuberculosis | No | Yes | No | Affects YscD puncta formation | (40) | |
| Salicylideneanilide C3 | Y. pseudotuberculosis | No | NT | No | Inhibits secretion and transcription | (13) | |
| Salicylideneanilide | EPEC | No | No | No | Inhibits T3SS transcription and EspB secretion | (26) | |
| Benzimidazole | Y. pseudotuberculosis | LcrF ‒ T3SS master regulator | No | No | Yes | Reduces cytotoxicity in infected cells; Protective in a murine model | (16) |
| C15, C19, C22, C24 and C38 |
Y. pseudotuberculosis P. aeruginosa |
No | No | No | Inhibits effector translocation | (18) | |
| C20 |
Y. pseudotuberculosis P. aeruginosa |
Suggested to interfere with adherence | No | No | No | Inhibits effector translocation | (18) |
| Compound D |
Y. pseudotuberculosis Yersinia pestis P. aeruginosa |
Suggested to target YopD ‒ translocon | NT | Yes | No | Inhibits effector secretion | (82) |
| Thiazolidinones |
S. enterica P. aeruginosa Yersinia Entercolitica Psuedomonas syringae |
Inhibits T2SS suggesting common target with T3SS such as secretin | No | No | Yes tobacco plants | Inhibits transcription and secretion; Reduces needle complex formation; Reduces hypersensitivity response in plant leaves | (83) |
| Phenoxyacetamides | P. aeruginosa | Suggested to target PscF ‒ needle protein | No | No | No | Isolation of PscF mutants resistant to phenoxyacetamide inhibitors | (34, 42, 43) |
| Phenoxyacetamides | P. aeruginosa | NT | NT | Yes | Reduces abscess size in mouse model of P. aeruginosa abscess formation | (44) | |
| Piericidins | Y. pseudotuberculosis | No | No | No | Inhibits T3SS-dependent NF-kB activation | (45) | |
| Piericidin A1 | Y. pseudotuberculosis | Suggested to target YscF-needle protein | NT | NT | No | Reduces number of needles present | (46) |
| Library of compounds | Salmonella spp. | SipD ‒ tip protein SipB ‒ translocon protein | NT | NT | No | Surface plasmon resonance screen to find compounds that bind to SipD and SipB | (48) |
| Library of compounds | Shigella spp. | IpaD ‒ tip protein | NT | NT | No | Surface plasmon resonance screen to find compounds that bind to IpaD | (49) |
| Malic diamide | Y. pseudotuberculosis | No | No | No | Inhibits secretion of YopB and YopD | (40) | |
| Flavonoids | S. enterica | Covalent labeling ofSPI-1 substrates | No | NT | No | Inhibits bacterial invasion of host cells | (47) |
| Compounds 7812, 7832, 7086 | Y. pestis | T3SS ATPase YscN | No; 7086 -Yes | No | No | Inhibits secretion | (84) |
| WEN05–03 | EPEC | T3SS ATPase EscN | No | No | No | Inhibits ATP hydrolysis; Reduces toxicity to infected HeLa cells | (29) |
| N-arylbenzylamines | C. trachomatis | Suggested to target T3SS ATPase SctN | No | No | No | Reduces secretion and chlamydial inclusions in host cells | (30) |
| Hydroxyquinolines INP1750INP1767 INP1855 |
C. trachomatis Y. pseudotuberculosis |
No | No | No | Inhibits cytotoxicity | (41) | |
| Hydroxyquinoline INP1855 |
P. aeruginosa | Suggested to target T3SS ATPase | No | No | Yes | Reduces cytotoxicity on host cells; Reduces bacterial burden and lung pathology in infected mice; Reduces activity of homologous T3SS ATPase YscN | (28) |
| Hydroxyquinoline INP1750 |
P. aeruginosa Y. pseudotuberculosis |
Suggested to target T3SS ATPase | No | No | No | Inhibits secretion and flagellar motility; Reduces activity of Yersinia T3SS ATPase YscN | (39) |
| Licoflavonol | S. enterica | No | NT | No | Reduces expression of chaperone sicA and invF-transcriptional regulator for SPI-1 effector proteins | (50) | |
| Epigallocatechin gallate | EPEC/EHEC S. enterica Y. pseudotuberculosis |
No | NT | No | Reduces adherence of EHEC/EPEC; Reduces Salmonella invasion into host cells; Reduces Yersinia induced cell death | (52) | |
| Epigallocatechin gallate | S. enterica | No | NT | No | Reduces Salmonella invasion into host cells | (51) | |
|
Psidium guajava leaf extract |
EPEC/EHEC S. enterica Y. pseudotuberculosis |
No | NT | No | Reduces adherence of EHEC/EPEC; Reduces Salmonella invasion into host cells; Reduces Yersinia induced cell death | (53) | |
| Sanguinarine chloride | S. enterica | No | Yes at higher conc. | No | Inhibits bacterial invasion of host cells | (54) | |
| Thymol | S. enterica | Slightly at higher conc. | Slightly at higher conc. | Yes | Inhibits bacterial invasion of host cells; Protects mice against infection | (85) | |
| Obovatol | S. enterica | No | NT | No | Reduces hemolysis of sheep red blood cells | (55) | |
| 7-hydroxycoumarin ‒ Umbelliferone |
Ralstonia solanacearum |
Yes(86) | NT | Yes tobacco plants | Reduces expression of T3SS effector genes; Reduces disease progression on tobacco plants | (87) | |
| SAHs | R. solanacearum | Minimal | NT | Yes tomato plants | Inhibits translocation; reduces bacterial growth on tomato plants | (56) | |
| SAHs | Erwinia amylovora | No | NT | Yes apple plants | Reduces expression of T3SS genes; reduces disease symptoms on apple plants | (57) | |
| Phenols | Xanthomonas oryzae | No | NT | Yes rice plants | Reduces expression of hrpG and hrpX-regulators of hrp genes which regulate T3SS effector expression; Reduces disease symptoms on rice plants | (58) | |
| Thiazolidin-2-cyanamide derivatives | X. oryzae | No | NT | Yes rice plants | Reduces expression of hrpG and hrpX-regulators of hrp genes which regulate T3SS effector expression; Reduces disease symptoms on rice plants | (59) |
NT = Not Tested; EHEC = Enterohemorrhagic Escherichia coli; EPEC = Enteropathogenic Escherichia coli; T3SS = Type III secretion system