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

Abstract

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

Keywords:

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

Acknowledgements

AP, SV, KS, SM, AS, VP, PN and SAP acknowledge SASTRA Deemed to be University, Thanjavur for extending support to use Schrödinger software suite for carrying out in silico studies and Professor Sumana MN (Department of Microbiology, JSS Medical College and JSS University, India) for the clinical S. aureus strains.

Disclosure statement

No potential conflict of interest was reported by the authors.

Funding

The author(s) reported there is no funding associated with the work featured in this article.

Author contributions

Study conception design and project administration: KS, PN and SAP; Computational data analysis and interpretation of results: AP, SV, SM, AS and KS; qsl-304 synthesis and characterization: AP and VP; in vitro data acquiring: AP; in vitro data analysis and interpretation of results: AP, SV, PN and SAP; Original draft manuscript preparation, writing, reviewing and editing: AP, SV, KS, PN and SAP. All authors have read and agreed to the published version of the manuscript.