Abstract
ABSTRACT Staphylococcus aureus (S. aureus) is one of the most serious human pathogens. α-Hemolysin (Hla) secreted by S. aureus is a key toxin for various infections. We herein report that Honokiol, a natural plant polyphenol, inhibits the secretion and hemolytic activity of staphylococcal Hla with concomitant growth inhibition of S. aureus and protection of S. aureus-mediated cell injury within subinhibitory concentrations. In parallel, Honokiol attenuates the staphylococcal Hla-induced inflammatory response by inhibiting NLRP3 inflammasome activation in vitro and in vivo. Consequently, the biologically active forms of the inflammatory cytokines IL-1β and IL-18 are reduced significantly in response to Honokiol in mice infected with S. aureus. Experimentally, we confirm that Honokiol binds to monomeric Hla with a modest affinity without impairing its oligomerization. Based on molecular docking analyses in silico, we make a theoretical discovery that Honokiol is located outside of the triangular region of monomeric Hla. The binding model restricts the function of the residues related to membrane channel formation, which leads to the functional disruption of the assembled membrane channel. This research creates a new paradigm for developing therapeutic agents against staphylococcal Hla-mediated infections.
Highlights
Staphylococcus aureus (S. aureus) is one of the most serious human pathogens [1]
Several lines of evidence have suggested that Hla production by S. aureus leads to the hemolysis of rabbit red blood cells, which are highly sensitive to the lytic action of Hla [14,15]
Several studies have reported that many natural products show protective effects against S. aureus injury by inhibiting the expression or activity of Hla [22,23]
Summary
Staphylococcus aureus (S. aureus) is one of the most serious human pathogens [1]. S. aureus infection is difficult to treat due to its resistance to a wide range of antibiotics [2,3]. The occurrence and nature of S. aureus infection critically depend on the various extracellular virulence factors secreted by S. aureus [4]. Α-Hemolysin (Hla) has emerged as an extracellular toxin secreted by most pathogenic S. aureu strains. It is selectively hemolytic and leads to cell damage through initial binding and incorporation into the target cell membrane [5]. The critical roles of Hla in S. aureus pathogenesis have been well documented in laboratory animals [6]. Inhibiting the function of Hla provides a paradigm shift to develop a new approach to treating S. aureus infections
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