Suppressing Alpha-Hemolysin as Potential Target to Screen of Flavonoids to Combat Bacterial Coinfection

Abstract

The rapid emergence of bacterial coinfection caused by cytosolic bacteria has become a huge threat to public health worldwide. Past efforts have been devoted to discover the broad-spectrum antibiotics, while the emergence of antibiotic resistance encourages the development of antibacterial agents. In essence, bacterial virulence is a factor in antibiotic tolerance. However, the discovery and development of new antibacterial drugs and special antitoxin drugs is much more difficult in the antibiotic resistance era. Herein, we hypothesize that antitoxin hemolytic activity can serve as a screening principle to select antibacterial drugs to combat coinfection from natural products. Being the most abundant natural drug of plant origins, flavonoids were selected to assess the ability of antibacterial coinfections in this paper. Firstly, we note that four flavonoids, namely, baicalin, catechin, kaempferol, and quercetin, have previously exhibited antibacterial abilities. Then, we found that baicalin, kaempferol, and quercetin have better inhibitions of hemolytic activity of Hla than catechin. In addition, kaempferol and quercetin, have therapeutic effectivity for the coinfections of Staphylococcus aureus and Pseudomonas aeruginosa in vitro and in vivo. Finally, our results indicated that kaempferol and quercetin therapied the bacterial coinfection by inhibiting S. aureus α-hemolysin (Hla) and reduced the host inflammatory response. These results suggest that antitoxins may play a promising role as a potential target for screening flavonoids to combat bacterial coinfection.

Antimicrobial Activity of Quercetin, Naringenin and Catechin: Flavonoids Inhibit Staphylococcus aureus-Induced Hemolysis and Modify Membranes of Bacteria and Erythrocytes

“…The αHL oligomer creates a hemolytic pore in the host cell membrane, which results in a loss of host cell integrity and cell death [ 38 , 39 ]. Recently, it was shown that some flavonoids (e.g., baicalin, kaempferol and quercetin) effectively inhibited the hemolytic activity of S. aureus αHL by modulating the expression of virulence factors [ 40 ]. In our experiments, we have shown for the first time another mechanism of quercetin’s antihemolytic activity, namely the ability to increase the resilience of the erythrocyte membrane to the toxin.…”

Dregs of Cardamine hupingshanensis as a feed additive to improve the egg quality

“…Natural herbal plants used as feed additives have extensive activities, including antioxidant, immune enhancement, anti-inflammation, etc ( 1 , 2 ). On account of these activities, natural plants have been widely used as feed additives to improve poultry growth and reproductive performance ( 3 , 4 ).…”

Antibacterial Modes of Herbal Flavonoids Combat Resistant Bacteria

“…For instance, as typical heat-clearing and damp eliminating herbs, Scutellariae Radix has the main flavonoes of baicalein and baicalin using the direct-acting antibacterial activity to fight against MRSA, S. aureus, and Streptococcus suis infections via inhibition of bacterial membrane functions ( Rajkumari et al, 2017 ; Chen et al, 2018 ; Zhang et al, 2020 ; Lu et al, 2021 ) ( Table 1 ). In addition, other flavonoid compounds in heat-clearing herbs also have the antibacterial abilities of damaging the bacterial membrane, such as quercetin from Gardeniae Fructus (iii, heat-clearing and damp eliminating herb) ( Mohamed et al, 2020 ; Yang et al, 2020 ), kaempferol origin from Moutan Coetrx (ii, heat-clearing and blood-eliminating herb) ( Lin et al, 2020 ; He et al, 2021 ), luteolin and lonicerin from Lonicerae Japonica (iv, heat-clearing and toxin-relieving herb) ( Zhang et al, 2018 ; Singh et al, 2021 ), hyperin and hyperoside origin from Lonicerae Japonica (iv, heat-clearing and toxin-relieving herb) ( Rodrigo Cavalcante de Araújo et al, 2019 ), rutin from Forshiae Fructus (iii, heat-clearing and damp eliminating herb) ( Deepika et al, 2019 ; Di Lodovico et al, 2020 ; Motallebi et al, 2020 ), and mangiferin from Anemarrhenae Rhizome (i, heat-clearing and blood-cooling herbs) ( Tchinda et al, 2019 ). These DAC IM flavonoids that treat bacterial strains are detailed in Table 1 .…”

“…It is worth noting that quercetin that belongs to flavanols have the inhibitory potential to effectively act as the efflux pump to treat CRNB due to its polyphenol hydroxyl group structure ( Pal and Tripathi, 2020 ). On the other side, flavonoid compounds have the direct-acting antibacterial effect of inhibiting bacterial virulence factors, such as α-hemolysin (Hla) of S. aureus ( Wang et al, 2020 ; He et al, 2021 ). The Hla can cause bacterial entry of host cells and also lead to bacterial coinfection, while flavonoids can target Hla to control bacterial infection ( He et al, 2021 ).…”

“…On the other side, flavonoid compounds have the direct-acting antibacterial effect of inhibiting bacterial virulence factors, such as α-hemolysin (Hla) of S. aureus ( Wang et al, 2020 ; He et al, 2021 ). The Hla can cause bacterial entry of host cells and also lead to bacterial coinfection, while flavonoids can target Hla to control bacterial infection ( He et al, 2021 ). Altogether, the flavonoid compounds that inhibit virulence factors are denoted as DAC IV flavonoids and summarized in Table 1 .…”