Abstract
Sortase A (SrtA) is a cysteine transpeptidase of most Gram-positive bacteria that is responsible for the anchorage of many surface protein virulence factors to the cell wall layer. SrtA mutants are unable to display surface proteins and are defective in the establishment of infections without affecting microbial viability. In this study, we report that quercitrin (QEN), a natural compound that does not affect Staphylococcus aureus growth, can inhibit the catalytic activity of SrtA in fibrinogen (Fg) cell-clumping and immobilized fibronectin (Fn) adhesion assays. Molecular dynamics simulations and mutagenesis assays suggest that QEN binds to the binding sites of the SrtA G167A and V193A mutants. These findings indicate that QEN is a potential lead compound for the development of new anti-virulence agents against S. aureus infections.
Highlights
The Gram-positive pathogenic bacteria, Staphylococcus aureus (S. aureus), is the most commonly isolated human bacterial pathogen, which persistently and asymptomatically colonizes up to 20%–30%of humans and intermittently colonizes up to 50%–60% [1]
Our results indicate that QEN is capable of effectively inhibiting the catalytic activity of Sortase A (SrtA), but has little effect on bacterial growth (Figure 1B,C)
Compared with traditional strategies that are aimed at killing bacteria or preventing their growth, this anti-virulence approach diminishes the rate of development of bacterial resistance
Summary
The Gram-positive pathogenic bacteria, Staphylococcus aureus (S. aureus), is the most commonly isolated human bacterial pathogen, which persistently and asymptomatically colonizes up to 20%–30%. Numerous previous studies using knockout experiments have demonstrated that the sortase A (SrtA) isoform is constitutively expressed and cleaves the amide bond between the threonine and glycine of the LPXTG motif, which is found in many surface proteins that fulfill diverse functions during the infection process [4]. SrtA inhibitors represent promising candidates for the development of therapeutics for the Gram-positive bacterial infections and may lead to new antibacterial drugs with novel mechanisms of action [10,11,12,13]. We observed that QEN, a natural bioflavonoid from Sabina pingii var. wilsonii that does not interfere with bacterial growth, could inhibit the catalytic activity of SrtA by binding directly to the active region of the SrtA, indicating that this agent may be a useful lead compound for developing novel antiinfective drugs
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
