Cytosporone B, an Inhibitor of the Type III Secretion System of Salmonella enterica Serovar Typhimurium

Abstract

bBacterial virulence factors have been increasingly regarded as attractive targets for development of novel antibacterial agents. Virulence inhibitors are less likely to generate bacterial resistance, which makes them superior to traditional antibiotics that target bacterial viability. Salmonella enterica serovar Typhimurium, an important food-borne human pathogen, has type III secretion system (T3SS) as its major virulence factor. T3SS secretes effector proteins to facilitate invasion into host cells. In this study, we identified several analogs of cytosporone B (Csn-B) that strongly block the secretion of Salmonella pathogenicity island 1 (SPI-1)-associated effector proteins, without affecting the secretion of flagellar protein FliC in vitro. Csn-B and two other derivatives exhibited a strong inhibitory effect on SPI-1-mediated invasion to HeLa cells, while no significant toxicity to bacteria was observed. Nucleoid proteins Hha and H-NS bind to the promoters of SPI-1 regulator genes hilD, hilC, and rtsA to repress their expression and consequently regulate the expression of SPI-1 apparatus and effector genes. We found that Csn-B upregulated the transcription of hha and hns, implying that Csn-B probably affected the secretion of effectors through the Hha-H-NS regulatory pathway. In summary, this study presented an effective SPI-1 inhibitor, Csn-B, which may have potential in drug development against antibiotic-resistant Salmonella.

NR4A1 is Involved in Fibrogenesis in Ovarian Endometriosis

“…Moreover, Csn-B does not have any such effects in NR4A1-null mice or cells, suggesting that Csn-B is an agonist of NR4A1 [27]. Recent studies found that Csn-B reduced hypercholesterolemia-induced inflammation [46], strongly blocked the secretion of Salmonella pathogenicity-associated proteins [55], and inhibited the growth of androgen-dependent bladder cancer cells [47]. In the present study, Csn-B effectively decreased the expression of fibrosis markers in vitro and attenuated fibrogenesis in a nude mouse model of endometriosis.…”

“…Strain HTF3 [55]. It specifically binds to the ligand-binding domain of NR4A1 and then stimulates the transactivational activity of NR4A1 [27].…”

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

“…Various compounds showing inhibition of T3SS-mediated hemolysis, such as aurodox and the gaudinomines, have also been identified (84, 85). Other compounds, such as salicylanilides, salicylideneanilines, sulfonylaminobenzanilides, cytosporone B, and citrus flavonoids are hypothesized to broadly inhibit T3SS gene transcription through unknown mechanisms (53, 64, 86–88). …”

“…Hydrophobicity and lipophilicity were shown to be important factors for inhibition of the T3SS by sulfonylaminobenzanilides (53). Cytosporone derivatives with extensive carbon chains containing a phenyl acetic acetate ester group were most potent (86). Derivatives of 8-hydroxyquinoline required a fused pyridine ring and an aromatic hydroxyl group for inhibition of T3SS function (119).…”

Proanthocyanidins in an astringent persimmon inhibit Salmonella pathogenicity island 1 (SPI1) secretion

“…We do not know how such a large molecule affects the SPI1 gene expression. The molecular mechanism of the suppression effect on SPI1 virulence factors might be similar with that of cytosporone B, which affected the secretion of SPI1 effectors through the Hha‐H‐NS regulatory pathway . But this has to be shown in our system.…”