English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

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 IC 50  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

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