Premium
Discovery of natural naphthoquinones as sortase A inhibitors and potential anti‐infective solutions against Staphylococcus aureus
Author(s) -
Nitulescu Georgiana,
Mihai Dragos P.,
Nicorescu Isabela M.,
Olaru Octavian T.,
Ungurianu Anca,
Zanfirescu Anca,
Nitulescu George M.,
Margina Denisa
Publication year - 2019
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.21599
Subject(s) - sortase a , staphylococcus aureus , plumbagin , chemistry , juglone , antimicrobial , enterococcus faecalis , microbiology and biotechnology , natural product , lawsone , naphthoquinone , biochemistry , stereochemistry , biology , bacteria , organic chemistry , genetics
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.