1. Discovery of natural naphthoquinones as sortase A inhibitors and potential anti-infective solutions against Staphylococcus aureus.
- Author
-
Nitulescu G, Mihai DP, Nicorescu IM, Olaru OT, Ungurianu A, Zanfirescu A, Nitulescu GM, and Margina D
- Subjects
- Aminoacyltransferases chemistry, Anti-Bacterial Agents chemistry, Bacterial Proteins chemistry, Biofilms drug effects, Catalytic Domain drug effects, Cysteine Endopeptidases chemistry, Cysteine Proteinase Inhibitors chemistry, Enterococcus faecalis drug effects, Enterococcus faecalis growth & development, Inhibitory Concentration 50, Models, Molecular, Molecular Docking Simulation, Naphthoquinones chemistry, Protein Binding, Staphylococcus aureus drug effects, Staphylococcus aureus enzymology, Staphylococcus epidermidis drug effects, Staphylococcus epidermidis growth & development, Aminoacyltransferases antagonists & inhibitors, Anti-Bacterial Agents pharmacology, Bacterial Proteins antagonists & inhibitors, Cysteine Proteinase Inhibitors pharmacology, Naphthoquinones pharmacology, Staphylococcus aureus growth & development
- Abstract
Three natural naphthoquinones were screened to find new anti-virulence agents as inhibitors against sortase A from Staphylococcus aureus (SaSrtA) by quantifying the increase in fluorescence intensity upon substrate cleavage at various concentrations. The 5-hydroxy-1,4-naphthalenedione derivatives, juglone and plumbagin, demonstrated a potent inhibitory effect, with IC
50 values of 1.78 μM, respectively, 16.71 μM. The related 2-hydroxy-1,4-naphthalenedione derivative, lawsone, demonstrated the selectivity of the chemical scaffold having no significant effect on SaSrtA. The experimental assay was reinforced by molecular docking experiments, antimicrobial, and toxicological studies. Molecular docking studies and the electrophilic character analysis suggest bonding to the enzyme active cysteine residue by a Michael addition reaction. None of the compounds had a significant effect on the concentration of total thiol proteins in the Daphnia magna toxicological assay after 24 hr exposure. Juglone and plumbagin moderately inhibited biofilm formation with no significant effect on bacterial growth of S. aureus, Enterococcus faecalis, and Staphylococcus epidermidis, indicating a selective anti-virulence profile., (© 2019 Wiley Periodicals, Inc.)- Published
- 2019
- Full Text
- View/download PDF