Acacetin Protects Mice from Staphylococcus aureus Bloodstream Infection by Inhibiting the Activity of Sortase A

Abstract

Staphylococcus aureus (S. aureus) is a major cause of infection in hospitals and communities.Widespread dissemination of multi-drug resistant S. aureus is a serious threat to the health of humans and animals. An anti-virulence strategy has been widely considered as an alternative therapeutic approach. Inhibitors of virulence factors are able to treat S. aureus infections without influencing the growth or viability of bacteria and rarely lead to bacterial resistance. Sortase A (SrtA) is a membrane-associated cysteine transpeptidase that catalyzes up to 25 surface proteins that covalently bind to cell wall peptidoglycans. In S. aureus, most of these surface proteins have been identified as important virulence factors that are vital in bacterial pathogenesis. In the present study, we show that acacetin, a natural flavonoid compound, inhibits the activity of SrtA in S. aureus (IC 50 = 36.46 ± 4.69 µg/mL, 128 µM) which affects the assembly of protein A (SpA) to cell walls and reduces the binding of S. aureus to fibrinogen (Fg). The mechanism of the interaction between acacetin and SrtA were preliminarily discussed using molecular dynamics simulations. The results suggested that acacetin adopted a compact conformation binding at the pocket of the SrtA via residues Arg-139 and Lys-140. By performing an animal infection model, we demonstrated that acacetin was able to protect mice from renal abscess formation induced by S. aureus and significantly increased survival rates. Taken together, these findings suggest that acacetin may be a promising candidate for the development of anti-S. aureus drugs.

Kaempferol Inhibits the Primary Attachment Phase of Biofilm Formation in Staphylococcus aureus

“…S. aureus surface proteins include clumping factors (ClfA and ClfB), which are essential for the adhesion of S. aureus to fibrinogen (Bi et al, 2016 ). These proteins are mainly anchored by sortase A to the cell wall and play significant roles in the formation of biofilms (Cascioferro et al, 2014 ).…”

“…The inhibitory effect of kaempferol on the activity of SrtA was measured based on the fluorescence changes. The sortase A (SrtA) activity inhibition assay was conducted according to a method described previously (Bi et al, 2016 ). The experiment was performed in black 96-well plates.…”

Salmonella Interacts With Autophagy to Offense or Defense

“…In recent years, accumulating studies have tried to find effective xenophagy-implicated agents to target Salmonella replication ( Table 2). It is well documented that many phenolic compounds, such as Carvacrol (Gaio et al, 2017), Thymol (Marchese et al, 2016), Quercetin (Wang et al, 2018), Resveratrol (Hwang and Lim, 2015), Acacetin (Bi et al, 2016), and Epigallocatechin gallate (Nakasone et al, 2017) exhibit antibacterial activity. Recently, Al Azzaz et al (2019) found that Resveratrol promotes the autophagy-dependent elimination of intracellular Salmonella both in vitro and in vivo.…”

Inhibitory effect of a natural phenolic compound, 3-p-trans-coumaroyl-2-hydroxyquinic acid against the attachment phase of biofilm formation of Staphylococcus aureus through targeting sortase A

“…These results were consistent with previous studies that reported many natural products exerted inhibitory effect on the adhesion of S. aureus to brinogen. 2,23,38,39 Hence, it can be inferred that CHQA might inhibit the attachment phase of biolm formation by affecting the adhesion of S. aureus to host surface, eventually lead to weak biolm formation.…”