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

Shui Liu,Xuming Deng,Yonglin Zhou,Tingting Wang,Jian Zhang,Xiaoxue Bai,Hong Zhang,Jianfeng Wang,Naiyu Hu,Xiaofeng Yang

doi:10.3389/fphar.2020.00179

Shui Liu, Xuming Deng + Show 8 more

Open Access

https://doi.org/10.3389/fphar.2020.00179

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Abstract

Clostridium perfringens (C. perfringens) type A strains are the main cause of gas gangrene in humans and animals. Treatment of this lethal disease is limited, and the prognosis is not good. Alpha-toxin (CPA) and perfringolysin O (PFO) secreted by C. perfringens play irreplaceable roles in cytotoxicity to host cells, persistence in host tissues, and lethality of gas gangrene pathology. This work determined the influence of amentoflavone, a biflavonoid isolated from Selaginella tamariscina and other plants, on hemolysis and cytotoxicity mediated by CPA and PFO and evaluated the in vivo therapeutic effect on gas gangrene. Our data showed that amentoflavone could block the hemolysis and cytotoxicity induced by CPA and PFO in vitro, thereby mediating significant protection against mortality of infected mice in a mouse gas gangrene model, efficient bacterial clearance in tissues and alleviation of histological damage in vivo. Based on the above results, amentoflavone may be a potential candidate against C. perfringens infection by reducing CPA and PFO-mediated virulence.

Highlights

Clostridium perfringens (C. perfringens) is a gram-positive, spore-forming, anaerobic bacterium that causes diverse diseases in both humans and animals, including gas gangrene, gastroenteritis, and necrotic enteritis (Kiu and Hall, 2018)
The IC50 value was 1.37 mg/ml to CPA and 2.50 mg/ml to perfringolysin O (PFO). These results indicated that amentoflavone is an effective inhibitor against both CPA and PFO
Studies have demonstrated the role of CPA and PFO in the development of gas gangrene and the synergistic effects of these two toxins in causing tissue damage and triggering disease (Awad et al, 2001; Verherstraeten et al, 2013)

Summary

Introduction

Clostridium perfringens (C. perfringens) is a gram-positive, spore-forming, anaerobic bacterium that causes diverse diseases in both humans and animals, including gas gangrene (clostridial myonecrosis), gastroenteritis, and necrotic enteritis (Kiu and Hall, 2018). C. perfringens is the most commonly identified cause of gas gangrene, a fatal disease caused by bacterial contamination in wounds (Stevens, 2000; Bryant and Stevens, 2010). Once the bacteria grow in tissues, the disease is followed by a very rapid spread. The incidence of gas gangrene is high during natural disasters, such as earthquakes (Chen et al, 2011; Stevens et al, 2012). Patients infected with gas gangrene from traumatic wounds or surgery treatment in disasters have a very high mortality rate (as high as 50–80%) (Wang et al, 2013).

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