Speaker
Description
Pseudomonas aeruginosa, an opportunistic and multidrug‑resistant pathogen, is a
leading cause of hospital‑acquired infections, including pneumonia. Its pathogenicity
is closely linked to quorum sensing (QS), a communication system that regulates
virulence factor production and biofilm formation through transcriptional regulators
such as LasR, RhlR, PqsR, and IqsR. Despite extensive efforts to identify QS
inhibitors, the molecular basis of QS protein–DNA interactions remain poorly
understood. This study aimed to characterize the interaction between LasR and the
promoter DNA of the hydrogen cyanide (hcn) virulence gene in P. aeruginosa at
atomic detail. Molecular modeling and structural analysis revealed that LasR
predominantly engages the DNA major groove, with Arg224, Arg222, and Phe210
among the key residues mediating sequence‑specific recognition. Autoinducer
binding and LasR dimerization were found to be critical for productive DNA
engagement, enabling conformations that optimize contact with target sequences. Multiple stable protein conformations involved in the DNA‑binding process were
identified, providing new insight into LasR’s functional dynamics. These findings
deepen our understanding of QS regulation at the protein–DNA interface and offer a
rational basis for inhibitor design. Potential strategies include targeting critical
DNA‑contact residues, disrupting dimerization, blocking autoinducer binding, or
directly interfering with DNA major groove accessibility. Such approaches could pave
the way for novel anti‑virulence therapeutics against multidrug‑resistant P. aeruginosa. Keywords: transcriptional regulators, autoinducer, dimerization, virulence factors, DNA major groove, inhibitor design.