Amentoflavone Ameliorates Streptococcus suis-Induced Infection In Vitro and In Vivo

Abstract

Streptococcus suis, an important zoonotic pathogen, has caused considerable economic losses in the swine industry and severe public health issues worldwide. The development of a novel effective strategy for the prevention and therapy of S. suis is urgently needed. Here, amentoflavone, a natural biflavonoid compound isolated from Chinese herbs that has negligible anti-S. suis activity, was identified as a potent antagonist of suilysin (SLY)-mediated hemolysis without interfering with the expression of SLY. Amentoflavone effectively inhibited SLY oligomerization, which is critical for its pore-forming activity. The treatment with amentoflavone reduced S. suis-induced cytotoxicity in macrophages (J774 cells). Furthermore, S. suis-infected mice that received amentoflavone exhibited lower mortality and bacterial burden. Additionally, amentoflavone significantly decreased the production of tumor necrosis factor alpha (TNF-␣), interleukin-1␤ (IL-1␤), and IL-6 in an S. suis-infected cell model. Analyses of signaling pathways demonstrated that amentoflavone reduced S. suisinduced inflammation in S. suis serotype 2 (SS2)-infected cells by regulating the p38, Jun N-terminal protein kinase 1 and 2 (JNK1/2), and NF-B pathways. The antivirulence and anti-inflammatory properties of amentoflavone against S. suis infection provide the possibility for future pharmaceutical application of amentoflavone in the treatment of S. suis infection. IMPORTANCEThe widespread use of antibiotics in therapy and in the prevention of Streptococcus suis infection in the swine industry raises concerns for the emergence of a resistant strain. The use of antivirulence agents has potential benefits, mainly because of the reduced selective pressure for the development of bacterial resistance. In this study, we found that amentoflavone is an effective agent against S. suis serotype 2 (SS2) infection both in vitro and in vivo. Our results demonstrated that amentoflavone is a promising anti-infective therapeutic for S. suis infections, due to its antivirulence and anti-inflammatory effects without antibacterial activity, with fewer side effects than conventional antibacterial agents.

Amentoflavone Attenuates Clostridium perfringens Gas Gangrene by Targeting Alpha-Toxin and Perfringolysin O

“…The finding that amentoflavone targets PFO activity was expected since PFO is also a member of the CDC family. Here, our data support the inhibitory effect of amentoflavone on CDC family toxins (Zhao et al, 2017;Shen et al, 2018).…”

“…Zhao et al reported the anticytotoxin effects of amentoflavone on pneumolysin, a devastating bacterial protein toxin of Streptococcus pneumoniae and a member of the CDC family (Alouf, 2000;Zhao et al, 2017). Besides, study of Shen et al showed that amentoflavone effectively inhibited suilysin-mediated hemolysis, a member of the CDC family toxin from Streptococcus suis (Shen et al, 2018). The finding that amentoflavone targets PFO activity was expected since PFO is also a member of the CDC family.…”

Analysis of Streptococcus agalactiae ‐induced liver injury in tilapia ( Oreochromis niloticus )

“…NF‐κB is a common transcription factor that is readily activated by inflammatory factors or growth factors (Maehara, Hasegawa, & Isobe, ; Meng & Cai, ; Yi, Tang, Yang, Chen, & Fei, ). Common inflammatory factors include IL‐1β and TNF‐α, which can activate NF‐κB (Shen, Niu, Li, Deng, & Wang, ; Yao & Sun, ). When NF‐κB is inactive, it forms a complex with IkB‐α, which is distributed in the cytoplasm.…”

“…Common inflammatory factors include IL-1β and TNF-α, which can activate NF-κB (Shen, Niu, Li, Deng, & Wang, 2018;Yao & Sun, 2019). When NF-κB is inactive, it forms a complex with IkB-α, which is distributed in the cytoplasm.…”

Isoalantolactone Enhances the Antimicrobial Activity of Penicillin G against Staphylococcus aureus by Inactivating β-Lactamase during Protein Translation

“…The circular dichroism (CD) spectra of the β-lactamases were analyzed using a CD spectrophotometer (MOS-500; Bio-Logic, France), according to the method described in our previous study [27]. E. coli BL21 (DE3) PET-28a β-lactamases expression was induced by IPTG in the presence or absence of IAL (32 µg/mL).…”