‘Computational studies on coumestrol-ArlR interaction to target ArlRS signaling cascade involved in MRSA virulence’

Abstract

Two component signaling system ArlRS (Autolysis-related locus) regulates adhesion, biofilm formation and virulence in methicillin resistant Staphylococcus aureus. It consists of a histidine kinase ArlS and response regulator ArlR. ArlR is composed of a N-terminal receiver domain and DNA-binding effector domain at C-terminal. ArlR receiver domain dimerizes upon signal recognition and activates DNA binding by effector domain and subsequent virulence expression. In silico simulation and structural data suggest that coumestrol, a phytochemical found in Pueraria montana, forges a strong intermolecular interaction with residues involved in dimer formation and destabilizes ArlR dimerization, an essential conformational switch required for downstream effector domain to bind to virulent loci. Structural and energy profiles of simulated ArlR-coumestrol complexes suggest lower affinity between ArlR monomers due to structural rigidity at the dimer interface hindering the conformational rearrangements relevant for dimer formation. These analyses could be an attractive strategy to develop therapeutics and potent leads molecules response regulators of two component systems in which are involved in MRSA virulence as well as other drug-resistant pathogens.

Communicated by Ramaswamy H. Sarma

Keywords:

• MRSA
• ArlR
• coumestrol
• molecular docking
• MD simulation

Acknowledgments

The authors acknowledge the support of the Internet of Things (IoT) and Data Communication Lab; Multiscale Simulation and Research Center (MSRC) Manipal University Jaipur for computational calculations. AKV acknowledges Ramdas Pai scholarship from MUJ. KNS is UGC SRF.

Authors’ contributions

Formal analysis, investigation – AKV, GJ, KNS, SKS; writing-review and editing – AKV, GJ, SKS; conceptualization, supervision, funding acquisition – SKS. All authors have read and agreed to the published version of the manuscript.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This work was supported by Science and Engineering Research Board (SERB), India grant CRG/2020/002008 to SKS.