Design, dynamic docking, synthesis, and in vitro validation of a novel DNA gyrase B inhibitor

Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-intermediate-resistant Staphylococcus aureus (VRSA) are among the WHO's high priority pathogens. Among these two, MRSA is the most globally documented pathogen that necessitates the pressing demand for new classes of anti-MRSA drugs. Bacterial gyrase targeted therapeutics are unique strategies to overcome cross-resistance as they are present only in bacteria and absent in higher eukaryotes. The GyrB subunit is essential for the catalytic functions of the Bacterial enzyme DNA Gyrase, thereby constituting a promising druggable target. The current study performed a structure-based virtual screening to designing GyrB target-specific candidate molecules. The de novo ligand design of novel hit molecules was performed using a rhodanine scaffold. Through a systematic in silico screening process, the hit molecules were screened for their synthetic accessibility, drug-likeness and pharmacokinetics properties in addition to its target specific interactions. Of the 374 hit molecules obtained through de novo ligand design, qsl-304 emerged as the most promising ligand. The molecular dynamic simulation studies confirmed the stable interaction between the key residues and qsl-304. qsl-304 was synthesized through a one-step chemical synthesis procedure, and the in vitro activity was proven, with an IC₅₀ of 31.23 µg/mL against the novobiocin resistant clinical isolate, Staphylococcus aureus sa-P2003. Further studies on time-kill kinetics showed the bacteriostatic nature with the diminished recurrence of resistance. The on-target gyrB inhibition further proved the efficacy of qsl-304.Communicated by Ramaswamy H. Sarma.

De novo-based drug design; Novobiocin; Rhodanine; Staphylococcus aureus; antibacterial resistance; gyrase inhibitor.