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<p>The BraSR two-component system plays a crucial role in bacitracin sensing and resistance in <i>Staphylococcus aureus</i>, making the BraS histidine kinase an attractive antibacterial target. In this study, we applied a structure-based drug discovery approach to identify ATP competitive isatin and indazole based hits targeting the BraS kinase domain. A two-stage virtual screening workflow, involving molecular docking, molecular dynamics simulations, MM-PBSA freeenergy estimation, and interaction analyses was used to prioritize compounds with favourable relative binding profiles within each series. Computational analyses suggested that several isatin and indazole derivatives adopt stable binding modes within the ATP-binding pocket of BraS and exhibit favourable predicted binding energetics compared to other screened compounds. Based on these in silico rankings, three isatin and three indazole derivatives were selected for chemical synthesis and experimental evaluation. Interactions between the test compounds and the recombinant BraS kinase domain were evaluated using microscale thermophoresis. Several compounds including IS7, IS12, IN16 and IN21 shows measurable binding affinities in the nanomolar range. The isatin-series compound IS12 exhibited a dissociation constant (Kd) of 2nM while IN21 from the indazole series exhibited a Kd of 251nM against the BraS kinase domain. In parallel, selected compounds were evaluated for their effects on biofilm formation using a crystal violet assay. Although a reduction in biofilm biomass was observed at specific concentrations, these effects are interpreted as indirect modulation of regulatory pathways associated with BraSR signalling rather than direct antibiofilm activity. Overall, this study identifies isatin and indazole derivatives as promising ATP-competitive hits that bind to the BraS kinase domain and provides a framework for further structure-guided optimization. However, functional inhibition, cellular efficacy, and pharmacological properties remain to be established through future biochemical and in vivo studies.</p>

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Targeting bacitracin resistance-associated histidine kinase (BraS) in MRSA with isatin and indazole derivatives

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月29日

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  • Grijesh Jaiswal,
  • Sandesh Telang,
  • Tripti Shrivastava,
  • Shantu Amin,
  • Arun K. Sharma,
  • Krishne Gowda,
  • Sandeep Kumar Srivastava

摘要

The BraSR two-component system plays a crucial role in bacitracin sensing and resistance in Staphylococcus aureus, making the BraS histidine kinase an attractive antibacterial target. In this study, we applied a structure-based drug discovery approach to identify ATP competitive isatin and indazole based hits targeting the BraS kinase domain. A two-stage virtual screening workflow, involving molecular docking, molecular dynamics simulations, MM-PBSA freeenergy estimation, and interaction analyses was used to prioritize compounds with favourable relative binding profiles within each series. Computational analyses suggested that several isatin and indazole derivatives adopt stable binding modes within the ATP-binding pocket of BraS and exhibit favourable predicted binding energetics compared to other screened compounds. Based on these in silico rankings, three isatin and three indazole derivatives were selected for chemical synthesis and experimental evaluation. Interactions between the test compounds and the recombinant BraS kinase domain were evaluated using microscale thermophoresis. Several compounds including IS7, IS12, IN16 and IN21 shows measurable binding affinities in the nanomolar range. The isatin-series compound IS12 exhibited a dissociation constant (Kd) of 2nM while IN21 from the indazole series exhibited a Kd of 251nM against the BraS kinase domain. In parallel, selected compounds were evaluated for their effects on biofilm formation using a crystal violet assay. Although a reduction in biofilm biomass was observed at specific concentrations, these effects are interpreted as indirect modulation of regulatory pathways associated with BraSR signalling rather than direct antibiofilm activity. Overall, this study identifies isatin and indazole derivatives as promising ATP-competitive hits that bind to the BraS kinase domain and provides a framework for further structure-guided optimization. However, functional inhibition, cellular efficacy, and pharmacological properties remain to be established through future biochemical and in vivo studies.