Abstract
The intractability of bacterial resistance presents a dilemma for therapies against Staphylococcus aureus (S. aureus) infection. Effective anti-virulence strategies are urgently needed, reflecting the proliferation of resistant strains. Inhibitors of sortase A (SrtA), enzymes that anchor virulence-related surface proteins, are regarded as promising candidates for countermeasures against bacterial infections. In the present study, the inhibitory effect of dryocrassin ABBA (ABBA) against SrtA and its molecular basis has been examined. Fluorescence resonance energy transfer (FRET) assays were used to determine the inhibitory activity of ABBA against SrtA. To identify the mechanism underlying this activity, molecular dynamics simulations and mutagenesis assays were applied, and the results revealed that the direct engagement of SrtA via ABBA through binding to V166 and V168 significantly attenuated the catalytic activity of SrtA. Taken together, these findings indicated that ABBA is a potential novel antimicrobial agent for S. aureus infection via targeting SrtA.
Highlights
Staphylococcus aureus (S. aureus), a Gram-positive bacteria identified in the 1880s, is the main etiological agent of multiple infectious diseases, playing a crucial role in skin and surgical site infections [1], simultaneously causing infective endocarditis, pleuropneumonia, osteomyelitis and bacteremia [2]
A majority of surface proteins that covalently bond to cell wall peptidoglycans are anchored through the same “housekeeping” enzyme, sortase A (SrtA) [10]
To successfully establish an infection, bacteria produce a variety of virulence factors, such as
Summary
Staphylococcus aureus (S. aureus), a Gram-positive bacteria identified in the 1880s, is the main etiological agent of multiple infectious diseases, playing a crucial role in skin and surgical site infections [1], simultaneously causing infective endocarditis, pleuropneumonia, osteomyelitis and bacteremia [2]. Cell surface proteins are vital virulence factors in S. aureus infections that enable bacteria to adhere, colonize and interact with their surrounding environment. Cys184, His120, Arg197, and Thr183 have been thereby tethering the C-terminal end of the polypeptide chain to the bacterial cell wall determined as indispensable in this process. Have that theof pathogenicity, as SrtA lethalmutants sepsis orsignificantly abscesses, was observed some cases virulence ofsuch some decreased in mouseinmodels, and of a staphylococcal partial loss of infections [19,20,21].such. Bacterial virulence factors could be ideal targets that hinder S. aureus infection [22], making a potential target. Further SrtA determine the based on the results of fluorescence resonance energy transfer (FRET). ABBA, as a potential inhibitor of enzyme activity, could be considered a candidate antimicrobial agent for S. aureus infection.
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