Abstract
The emergence and wide spread of multi-drug resistant Staphylococcus aureus (S. aureus) requires the development of new therapeutic agents with alternative modes of action. Anti-virulence strategies are hoped to meet that need. Sortase A (SrtA) has attracted great interest as a potential drug target to treat infections caused by S. aureus, as many of the surface proteins displayed by SrtA function as virulence factors by mediating bacterial adhesion to specific organ tissues, invasion of host cells, and evasion of the host-immune responses. It has been suggested that inhibitors of SrtA might be promising candidates for the treatment and/or prevention of S. aureus infections. In this study, we report that chlorogenic acid (CHA), a natural compound that lacks significant anti-S. aureus activity, inhibit the activity of SrtA in vitro (IC50 = 33.86 ± 5.55 μg/ml) and the binding of S. aureus to fibrinogen (Fg). Using molecular dynamics simulations and mutagenesis assays, we further demonstrate that CHA binds to the binding sites of C184 and G192 in the SrtA. In vivo studies demonstrated that CHA prevent mice from S. aureus-induced renal abscess, resulting in a significant survival advantage. These findings indicate that CHA is a promising therapeutic compound against SrtA during S. aureus infections.
Highlights
Staphylococcus aureus (S. aureus) is an opportunistic pathogen which produces a wide spectrum of diseases, ranging from minor skin infections and soft tissue infections to bacteraemia and toxic shock syndrome
chlorogenic acid (CHA) is an ester formed between quinic acid and trans-cinnamic acid, which represents a new class of Sortase A (SrtA) inhibitor (Figure 1A)
The results indicate that CHA could be a potential anti-virulence molecule which could effectively inhibit SrtA activity at a concentration far lower than the minimum inhibitory concentrations (MICs)
Summary
Staphylococcus aureus (S. aureus) is an opportunistic pathogen which produces a wide spectrum of diseases, ranging from minor skin infections and soft tissue infections to bacteraemia and toxic shock syndrome. S. aureus is recognized as a prominent pathogen and has developed a wide range of resistance to antibiotics (such as methicillin and vancomycin), as well as causing severe clinical complications and poor outcomes (Vincent et al, 2006; Naber, 2009), making treatment options difficult. The prevalence of the antibiotic -resistant S. aureus isolates indicates the need for alternative therapy to treat these infections (Ton-That and Schneewind, 1999). The virulence factors of pathogens play a key role in the establishment of an infection. The ability of S. aureus to cause disease has been generally attributed to two classes of virulence
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