Abstract:
Pseudomonas aeruginosa is one of the most dangerous superbugs and is responsible
for both acute and chronic infection. Current therapies are not effective because of
biofilms that increase antibiotic resistance. Biofilm formation is regulated through a
system called quorum sensing, and includes transcriptional regulators LasR and RhIR.
These regulators are activated by their own natural autoinducers. Targeting quorum
sensing is a promising strategy to combat bacterial pathogenicity. Flavonoids are very
well known for their antimicrobial activity and inhibit Pseudomonas aeruginosa biofilm
formation, but the mechanism of action is unknown. In the present study, we analyze the
mode of interactions of LasR with taxifolin. We use a combination of molecular docking,
molecular dynamics simulations to study the interaction of LasR with taxifolin. We show
that taxifolin has two binding modes. One binding mode is the interaction with ligandbinding
domain. The second mode is the interaction with the “bridge”, which is a cryptic
site. Biochemical studies show hydroxyl group of ring A in flavonoids is necessary for
inhibition. In our model the hydroxyl group ensures the formation of hydrogen bonds
during the second binding mode. This study may offer insights on how taxifolin inhibits
LasR and the quorum sensing circuitry.